Novel compounds as diacylglycerol acyltransferase inhibitors

ABSTRACT

This invention relates to novel compounds which are inhibitors of acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT-1), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination with weight management therapies or other triglyceride lowering therapy for the prevention or treatment of diseases related to DGAT-1 dysfunction or where modulation of DGAT-1 activity may have therapeutic benefit including but not limited to obesity, obesity related disorders, genetic (Type 1, Type 5 hyperlipidemia) and acquired forms of hypertriglyceridemia or hyperlipoproteinemia-related disorders, caused by but not limited to lipodystrophy, hypothyroidism, medications (beta blockers, thiazides, estrogen, glucocorticoids, transplant) and other factors (pregnancy, alcohol intake), hyperlipoproteinemia, chylomicronemia, dyslipidemia, non-alcoholic steatohepatitis, diabetes, insulin resistance, metabolic syndrome, cardiovascular outcomes, angina, excess hair growth (including syndromes associated with hirsutism), nephrotic syndrome, fibrosis such as myocardial, renal and liver fibrosis, hepatitis C virus infection and acne or other skin disorders.

FIELD OF INVENTION

This invention relates to novel compounds which are inhibitors of acylcoenzyme A: diacylglycerol acyltransferase 1 (DGAT-1), to pharmaceuticalcompositions containing them, to processes for their preparation, and totheir use in therapy, alone or in combination with weight managementtherapies or other triglyceride lowering therapy, for the prevention ortreatment of diseases related to DGAT-1 dysfunction or where modulationof DGAT-1 activity may have therapeutic benefit including but notlimited to obesity, obesity related disorders, genetic (Type 1, Type 5hyperlipidemia) and acquired forms of hypertriglyceridemia orhyperlipoproteinemia-related disorders, caused by but not limited tolipodystrophy, hypothyroidism, medications (beta blockers, thiazides,estrogen, glucocorticoids, transplant) and other factors (pregnancy,alcohol intake), hyperlipoproteinemia, chylomicronemia, dyslipidemia,non-alcoholic steatohepatitis, diabetes, insulin resistance, metabolicsyndrome, cardiovascular outcomes, angina, excess hair growth (includingsyndromes associated with hirsutism), nephrotic syndrome, fibrosis suchas myocardial, renal and liver fibrosis, hepatitis C virus infection andacne or other skin disorders.

BACKGROUND OF THE INVENTION

Obesity is a medical condition that is reaching epidemic proportionsamong humans in a number of countries throughout the world. It is acondition that is also associated with or induces other diseases orconditions that disrupt life activities and lifestyles. Obesity isrecognized as a serious risk factor for other diseases and conditionssuch as diabetes, hypertension, and arteriosclerosis. It is also knownthat increased body weight due to obesity can place a burden on joints,such as knee joints, causing arthritis, pain, and stiffness.

Because overeating and obesity have become such a problem in the generalpopulation, many individuals are now interested in losing weight,reducing weight, and maintaining a healthy body weight and desirablelifestyle. One approach to treating obesity is to reduce food intakeand/or hyperlipidemia. It has been suggested that molecules which aredeveloped to prevent the accumulation of triglyceride would not onlyreduce obesity but also have the additional beneficial effect ofreducing insulin resistance, a primary factor contributing to thedevelopment of diabetes.

Acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT-1) is one of twoknown DGAT enzymes that catalyze the final step in mammaliantriglyceride synthesis. DGAT-1 is an enzyme that is implicated in thedevelopment of both diabetes and insulin resistance. Studies of DGAT-1deficient mice show that DGAT-1 deficiency protects against insulinresistance and obesity, see Chen, H. C. et al., J Clin Invest., 109(8),1049-1055 (2002). Therefore, inhibitors of DGAT-1 should be useful forthe treatment of metabolic disorders, e.g. obesity, Type 2 diabetes, andinsulin resistance syndrome (or metabolic syndrome) and other associatedor related diseases and conditions.

SUMMARY OF THE INVENTION

This invention relates to compounds of Formula (I) or pharmaceuticallyacceptable salts thereof:

wherein:

X is CH, CR², or N;

R¹ is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, 4- to 6-memberedheterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, wherein said(C₁-C₄)alkyl is optionally substituted by hydroxyl, (C₁-C₄)alkoxy,—CO₂H, or —CO₂(C₁-C₄)alkyl, and wherein said phenyl or 5- or 6-memberedheteroaryl is optionally substituted by —O(C₁-C₂)alkylO- or optionallysubstituted with one to three substituents independently selected fromhalogen, cyano, oxo, hydroxyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,(C₃-C₇)cycloalkoxy, phenyl(C₁-C₂)alkoxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, —CO₂H, and —CO₂(C₁-C₄)alkyl; and

R² is halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, 4- to6-membered heterocycloalkyl, —NHC(O)(C₁-C₄)alkyl, or—NHC(O)(C₃-C₇)cycloalkyl;

provided that the compound is not4-amino-6-(1-propyl-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,3-(5-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-1H-indol-1-yl)propanoicacid,4-amino-6-(1-(3-methoxypropyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-methyl-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(2-methoxyethyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-isopropyl-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-propyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-cyclopropyl-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-phenyl-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(3-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(3-chlorophenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,6-amino-4-(7-(2-methoxyphenyl)-7H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydropyrimido[5,4-f][1,4]oxazepin-5(2H)-one,4-amino-6-(1-(2-methoxyphenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(3,4-difluorophenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(2-fluorophenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(3-(trifluoromethyl)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(thiazol-2-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(pyridin-2-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(pyrazin-2-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(6-methylpyridin-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(4-(difluoromethyl)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,4-amino-6-(1-(4-(difluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one,or4-amino-6-(1-(4-(trifluoromethyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one.

This invention also relates to a pharmaceutical composition comprising acompound of Formula (I) and a pharmaceutically acceptable excipient.

This invention also relates to a method of treating obesity comprisingadministering to a human in need thereof an effective amount of acompound of Formula (I) or a pharmaceutically acceptable salt thereof.

DETAIL DESCRIPTION OF THE INVENTION

This invention relates to compounds of the Formula (I) as defined above.

In another embodiment, this invention relates to compounds of Formula(I) wherein X is CH or CR². In a specific embodiment, this inventionrelates to compounds of Formula (I) wherein X is CH. In another specificembodiment, this invention relates to compounds of Formula (I) wherein Xis N.

In another embodiment, this invention relates to compounds of Formula(I) wherein R² is (C₃-C₇)cycloalkyl, 4- to 6-membered heterocycloalkyl,or —NHC(O)(C₃-C₇)cycloalkyl. In a specific embodiment, this inventionrelates to compounds of Formula (I) wherein R² is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, —NHC(O)cyclopropyl, —NHC(O)cyclobutyl,—NHC(O)cyclopentyl, or —NHC(O)cyclohexyl. In a more specific embodiment,this invention relates to compounds of Formula (I) wherein R² iscyclopropyl, morpholinyl, or —NHC(O)cyclopropyl.

In another specific embodiment, this invention relates to compounds ofFormula (I) wherein R² is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl. In a more specific embodiment, this invention relates tocompounds of Formula (I) wherein R² is cyclopropyl.

In another specific embodiment, this invention relates to compounds ofFormula (I) wherein R² is azetidinyl, oxetanyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, ortetrahydropyranyl. In a more specific embodiment, this invention relatesto compounds of Formula (I) wherein R² is morpholinyl.

In another specific embodiment, this invention relates to compounds ofFormula (I) wherein R² is —NHC(O)cyclopropyl, —NHC(O)cyclobutyl,—NHC(O)cyclopentyl, or —NHC(O)cyclohexyl. In a more specific embodiment,this invention relates to compounds of Formula (I) wherein R² is—NHC(O)cyclopropyl.

In another embodiment, this invention relates to compounds of Formula(I) wherein R¹ is (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, ortriazinyl is optionally substituted with one or two substituentsindependently selected from chlorine, bromine, methyl, ethyl,trifluoromethyl, oxo, hydroxyl, methoxy, ethoxy, isopropyloxy,isobutyloxy, difluoromethoxy, trifluoromethoxy, and cyclopentyloxy. Inanother embodiment, this invention relates to compounds of Formula (I)wherein R¹ is (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, ortriazinyl is optionally substituted with one or two substituentsindependently selected from chlorine, methyl, trifluoromethyl, oxo,hydroxyl, methoxy, ethoxy, isopropyloxy, isobutyloxy, difluoromethoxy,trifluoromethoxy, and cyclopentyloxy. In a specific embodiment, thisinvention relates to compounds of Formula (I) wherein R¹ is n-propyl,isopropyl, 2-hydroxy-2-methyl-prop-1-yl, cyclobutyl, oxetanyl,tetrahydropyranyl, 2-ethylphenyl, 2,3-dichlorophenyl,3,5-dichlorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl,2-isopropyloxyphenyl, 3-isobutyloxyphenyl, 3-difluoromethoxyphenyl,2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl,2-methoxy-4-methylphenyl, 2-methoxy-4-trifluoromethylphenyl,3-chloro-2-methoxyphenyl, 2-bromo-3-methoxyphenyl,2-cyclopentyloxyphenyl, 5-methyl-1,3,4-oxadiazol-2-yl,5-methyl-1,3,4-triazol-2-yl, 6-methylpyridin-3-yl,2-methoxy-6-methylpyridin-3-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl,2-methylpyrimidin-5-yl, 2-ethylpyrimidin-5-yl, 2-methoxypyrimidin-5-yl,or 5-methylpyrazin-2-yl. In another specific embodiment, this inventionrelates to compounds of Formula (I) wherein R¹ is n-propyl, isopropyl,2-hydroxy-2-methyl-prop-1-yl, cyclobutyl, oxetanyl, 2,3-dichlorophenyl,3,5-dichlorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl,2-isopropyloxyphenyl, 3-isobutyloxyphenyl, 3-difluoromethoxyphenyl,2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl,2-methoxy-4-trifluoromethylphenyl, 2-cyclopentyloxyphenyl,5-methyl-1,3,4-oxadiazol-2-yl, 6-methylpyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl, or 2-methylpyrimidin-5-yl.

In another embodiment, this invention relates to compounds of Formula(I) wherein R¹ is (C₁-C₄)alkyl which is optionally substituted byhydroxyl, (C₁-C₄)alkoxy, —CO₂H, or —CO₂(C₁-C₄)alkyl. In anotherembodiment, this invention relates to compounds of Formula (I) whereinR¹ is (C₁-C₄)alkyl or hydroxy(C₁-C₄)alkyl. In a specific embodiment,this invention relates to compounds of Formula (I) wherein R¹ isn-propyl, isopropyl, or 2-hydroxy-2-methyl-prop-1-yl.

In another embodiment, this invention relates to compounds of Formula(I) wherein R¹ is (C₃-C₇)cycloalkyl or 4- to 6-memberedheterocycloalkyl. In a specific embodiment, this invention relates tocompounds of Formula (I) wherein R¹ is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, ortetrahydropyranyl. In another specific embodiment, this inventionrelates to compounds of Formula (I) wherein R¹ is cyclobutyl, oxetanyl,or tetrahydropyranyl. In a more specific embodiment, this inventionrelates to compounds of Formula (I) wherein R¹ is cyclobutyl oroxetanyl.

In another embodiment, this invention relates to compounds of Formula(I) wherein R¹ is phenyl, furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, or triazinyl, each of which is optionallysubstituted by —O(C₁-C₂)alkylO- or optionally substituted with one tothree substituents independently selected from halogen, cyano, oxo,hydroxyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, (C₃-C₇)cycloalkoxy,phenyl(C₁-C₂)alkoxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, —CO₂H, and —CO₂(C₁-C₄)alkyl. In another embodiment,this invention relates to compounds of Formula (I) wherein R¹ is phenyl,furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, ortriazinyl, each of which is optionally substituted with one or twosubstituents independently selected from chlorine, bromine, methyl,ethyl, trifluoromethyl, oxo, hydroxyl, methoxy, ethoxy, isopropyloxy,isobutyloxy, difluoromethoxy, trifluoromethoxy, and cyclopentyloxy. Inanother embodiment, this invention relates to compounds of Formula (I)wherein R¹ is phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl,pyrimidinyl, or triazinyl, each of which is optionally substituted withone or two substituents independently selected from chlorine, methyl,trifluoromethyl, oxo, hydroxyl, methoxy, ethoxy, isopropyloxy,isobutyloxy, difluoromethoxy, trifluoromethoxy, and cyclopentyloxy.

In another embodiment, this invention relates to compounds of Formula(I) wherein R¹ is phenyl which is optionally substituted by—O(C₁-C₂)alkylO- or optionally substituted with one to threesubstituents independently selected from halogen, cyano, oxo, hydroxyl,(C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, (C₃-C₇)cycloalkoxy,phenyl(C₁-C₂)alkoxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, —CO₂H, and —CO₂(C₁-C₄)alkyl. In another embodiment,this invention relates to compounds of Formula (I) wherein R¹ is phenylwhich is optionally substituted by —O(C₁-C₂)alkylO- or optionallysubstituted with one or two substituents independently selected fromfluorine, chlorine, hydroxyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,(C₃-C₇)cycloalkoxy, (C₁-C₄)alkyl, and halo(C₁-C₄)alkyl. In anotherembodiment, this invention relates to compounds of Formula (I) whereinR¹ is phenyl which is optionally substituted with one or twosubstituents independently selected from chlorine, bromine, methyl,ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, isopropyloxy,isobutyloxy, difluoromethoxy, trifluoromethoxy, and cyclopentyloxy. Inanother embodiment, this invention relates to compounds of Formula (I)wherein R¹ is phenyl which is optionally substituted with one or twosubstituents independently selected from chlorine, methyl,trifluoromethyl, hydroxyl, methoxy, ethoxy, isopropyloxy, isobutyloxy,difluoromethoxy, trifluoromethoxy, and cyclopentyloxy. In a specificembodiment, this invention relates to compounds of Formula (I) whereinR¹ is 2-ethylphenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,2-hydroxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-isopropyloxyphenyl,3-isobutyloxyphenyl, 3-difluoromethoxyphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 2-methoxy-4-methylphenyl,2-methoxy-4-trifluoromethylphenyl, 3-chloro-2-methoxyphenyl,2-bromo-3-methoxyphenyl, or 2-cyclopentyloxyphenyl. In another specificembodiment, this invention relates to compounds of Formula (I) whereinR¹ is 2,3-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl,2-methoxyphenyl, 2-ethoxyphenyl, 2-isopropyloxyphenyl,3-isobutyloxyphenyl, 3-difluoromethoxyphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 2-methoxy-4-trifluoromethylphenyl, or2-cyclopentyloxyphenyl.

In another embodiment, this invention relates to compounds of Formula(I) wherein R¹ is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl, or isothiazolyl, each of which is optionally substitutedwith one or two substituents independently selected from hydroxyl,(C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, (C₃-C₇)cycloalkoxy, (C₁-C₄)alkyl, andhalo(C₁-C₄)alkyl. In another embodiment, this invention relates tocompounds of Formula (I) wherein R¹ is furanyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiadiazolyl, or isothiazolyl, each of which isoptionally substituted with one or two substituents independentlyselected from methyl, trifluoromethyl, hydroxyl, methoxy, ethoxy,isopropyloxy, isobutyloxy, difluoromethoxy, trifluoromethoxy, andcyclopentyloxy. In a specific embodiment, this invention relates tocompounds of Formula (I) wherein R¹ is 5-methyl-1,3,4-oxadiazol-2-yl or5-methyl-1,3,4-triazol-2-yl. In another specific embodiment, thisinvention relates to compounds of Formula (I) wherein R¹ is5-methyl-1,3,4-oxadiazol-2-yl.

In another embodiment, this invention relates to compounds of Formula(I) wherein R¹ is pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl,each of which is optionally substituted with one or two substituentsindependently selected from oxo, hydroxyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, (C₃-C₇)cycloalkoxy, (C₁-C₄)alkyl, andhalo(C₁-C₄)alkyl. In another embodiment, this invention relates tocompounds of Formula (I) wherein R¹ is pyridinyl, pyridazinyl,pyrazinyl, or pyrimidinyl, each of which is optionally substituted withone or two substituents independently selected from methyl,trifluoromethyl, hydroxyl, oxo, methoxy, ethoxy, isopropyloxy,isobutyloxy, difluoromethoxy, trifluoromethoxy, and cyclopentyloxy. In aspecific embodiment, this invention relates to compounds of Formula (I)wherein R¹ is 6-methylpyridin-3-yl, 2-methoxy-6-methylpyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 2-methylpyrimidin-5-yl,2-ethylpyrimidin-5-yl, 2-methoxypyrimidin-5-yl, or 5-methylpyrazin-2-yl.In another specific embodiment, this invention relates to compounds ofFormula (I) wherein R¹ is 6-methylpyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl, or 2-methylpyrimidin-5-yl.

In a particular embodiment, this invention relates to compounds ofFormula (I) or pharmaceutically acceptable salts thereof wherein:

X is CH or CR²;

R¹ is (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, ortriazinyl is optionally substituted with one or two substituentsindependently selected from chlorine, bromine, methyl, ethyl,trifluoromethyl, oxo, hydroxyl, methoxy, ethoxy, isopropyloxy,isobutyloxy, difluoromethoxy, trifluoromethoxy, and cyclopentyloxy; and

R² is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl,oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, tetrahydropyranyl, —NHC(O)cyclopropyl,—NHC(O)cyclobutyl, —NHC(O)cyclopentyl, or —NHC(O)cyclohexyl.

In a particular embodiment, this invention relates to compounds ofFormula (I) or pharmaceutically acceptable salts thereof wherein:

X is CH or CR²;

R¹ is (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, ortriazinyl is optionally substituted with one or two substituentsindependently selected from chlorine, methyl, trifluoromethyl, oxo,hydroxyl, methoxy, ethoxy, isopropyloxy, isobutyloxy, difluoromethoxy,trifluoromethoxy, and cyclopentyloxy; and

R² is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl,oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, tetrahydropyranyl, —NHC(O)cyclopropyl,—NHC(O)cyclobutyl, —NHC(O)cyclopentyl, or —NHC(O)cyclohexyl.

In a particular embodiment, this invention relates to compounds ofFormula (I) or pharmaceutically acceptable salts thereof wherein:

X is CH; and

R¹ is (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, ortriazinyl is optionally substituted with one or two substituentsindependently selected from chlorine, methyl, trifluoromethyl, oxo,hydroxyl, methoxy, ethoxy, isopropyloxy, isobutyloxy, difluoromethoxy,trifluoromethoxy, and cyclopentyloxy.

In a particular embodiment, this invention relates to compounds ofFormula (I) or pharmaceutically acceptable salts thereof wherein:

X is N;

R¹ is (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, ortriazinyl is optionally substituted with one or two substituentsindependently selected from chlorine, methyl, trifluoromethyl, oxo,hydroxyl, methoxy, ethoxy, isopropyloxy, isobutyloxy, difluoromethoxy,trifluoromethoxy, and cyclopentyloxy.

This invention also relates to compounds that are exemplified in theExperimental section.

Specific compounds of this invention include:

-   4-amino-6-(1-(oxetan-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(3-(trifluoromethoxy)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5    (6H)-one;-   4-amino-6-(1-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5    (6H)-one;-   4-amino-6-(1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5    (6H)-one;-   4-amino-6-(1-(2-(trifluoromethoxy)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5    (6H)-one;-   4-amino-6-(1-(2-methoxy-4-(trifluoromethyl)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(3-(difluoromethoxy)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5    (6H)-one;-   4-amino-6-(1-(3-isobutoxyphenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5    (6H)-one;-   4-amino-6-(1-(2-isopropoxyphenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5    (6H)-one;-   4-amino-6-(1-(3,5-dichlorophenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5    (6H)-one;-   4-amino-6-(1-(3,5-dichlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(2,3-dichlorophenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5    (6H)-one;-   4-amino-6-(1-(2-methylpyrimidin-5-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5    (6H)-one;-   4-amino-6-(1-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(2-hydroxyphenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(2-(cyclopentyloxy)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(2-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(2-(cyclopentyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(2-ethoxyphenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(7-cyclopropyl-1-propyl-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   N-(5-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-1-(2-methoxyphenyl)-1H-indol-7-yl)cyclopropanecarboxamide;-   4-amino-6-(1-isopropyl-7-morpholino-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   N-(5-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-1-isopropyl-1H-indol-7-yl)cyclopropanecarboxamide;-   4-amino-6-(7-cyclopropyl-1-(6-methylpyridin-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(2-ethylpyrimidin-5-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(3-chloro-2-methoxyphenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(2-methoxy-4-methylphenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(2-methoxy-6-methylpyridin-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(2-methoxypyrimidin-5-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(2-ethylphenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(5-methylpyrazin-2-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one;-   4-amino-6-(1-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-][1,4]oxazepin-5(6H)-one;    and-   4-amino-6-(1-(2-bromo-3-methoxyphenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5    (6H)-one;

or pharmaceutically acceptable salts thereof.

A person of ordinary skills in the art recognizes that compounds of thepresent invention may have alternative names when different namingsoftware is used.

This invention also relates to compounds of Formula (I) or any of theexemplified compounds, or their pharmaceutically acceptable saltsthereof, for use in therapy. In particular, for use in the treatment ofdiseases mediated by Acyl coenzyme A: diacylglycerol acyltransferase 1(DGAT-1), such as obesity, obesity related disorders, genetic (Type 1,Type 5 hyperlipidemia) and acquired forms of hypertriglyceridemia orhyperlipoproteinemia-related disorders, hyperlipoproteinemia,chylomicronemia, dyslipidemia, non-alcoholic steatohepatitis, diabetes,insulin resistance, metabolic syndrome, cardiovascular outcomes, angina,excess hair growth (including syndromes associated with hirsutism),nephrotic syndrome, fibrosis such as mycocardial, renal and liverfibrosis, hepatitis C virus infection and acne or other skin disorders.In particular, this invention relates to compounds of Formula (I), orany of the exemplified compounds, or their pharmaceutically acceptablesalts thereof, for use in the treatment of obesity.

This invention also relates to compounds of Formula (I) or any of theexemplified compounds, or their pharmaceutically acceptable saltsthereof, for use as a medicament. This invention also relates tocompounds of Formula (I) or any of the exemplified compounds, or theirpharmaceutically acceptable salts thereof, in the manufacture of amedicament for the treatment of obesity.

Typically, but not absolutely, the salts of the present invention arepharmaceutically acceptable salts. Salts encompassed within the term“pharmaceutically acceptable salts” refer to non-toxic salts of thecompounds of this invention. Salts of the disclosed compounds containinga basic amine or other basic functional group may be prepared by anysuitable method known in the art, including treatment of the free basewith an inorganic acid, such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like, or with anorganic acid, such as acetic acid, trifluoroacetic acid, maleic acid,succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such asglucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citricacid or tartaric acid, amino acid, such as aspartic acid or glutamicacid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonicacid, such as p-toluenesulfonic acid, methanesulfonic acid,ethanesulfonic acid or the like. Examples of pharmaceutically acceptablesalts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,phosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates,phenylpropionates, phenylbutrates, citrates, lactates,γ-hydroxybutyrates, glycolates, tartrates mandelates, and sulfonates,such as xylenesulfonates, methanesulfonates, propanesulfonates,naphthalene-1-sulfonates and naphthalene-2-sulfonates.

Salts of the disclosed compounds containing a carboxylic acid or otheracidic functional group can be prepared by reacting with a suitablebase. Such a pharmaceutically acceptable salt may be made with a basewhich affords a pharmaceutically acceptable cation, which includesalkali metal salts (especially sodium and potassium), alkaline earthmetal salts (especially calcium and magnesium), aluminum salts andammonium salts, as well as salts made from physiologically acceptableorganic bases such as trimethylamine, triethylamine, morpholine,pyridine, piperidine, picoline, dicyclohexylamine,N,N′-dibenzylethylenediamine, 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine,dibenzylpiperidine, dehydroabietylamine, N,N′-bisdehydroabietylamine,glucamine, N-methylglucamine, collidine, choline, quinine, quinoline,and basic amino acid such as lysine and arginine.

Other salts, which are not pharmaceutically acceptable, may be useful inthe preparation of compounds of this invention and these should beconsidered to form a further aspect of the invention. These salts, suchas oxalic or trifluoroacetate, while not in themselves pharmaceuticallyacceptable, may be useful in the preparation of salts useful asintermediates in obtaining the compounds of the invention and theirpharmaceutically acceptable salts.

As used herein, the term “a compound of Formula (I)” or “the compound ofFormula (I)” refers to one or more compounds according to Formula (I).The compound of Formula (I) may exist in solid or liquid form. In thesolid state, it may exist in crystalline or noncrystalline form, or as amixture thereof. The skilled artisan will appreciate thatpharmaceutically acceptable solvates may be formed for crystalline ornon-crystalline compounds. In crystalline solvates, solvent moleculesare incorporated into the crystalline lattice during crystallization.Solvates may involve non-aqueous solvents such as, but not limited to,ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate,or they may involve water as the solvent that is incorporated into thecrystalline lattice. Solvates wherein water is the solvent incorporatedinto the crystalline lattice are typically referred to as “hydrates.”Hydrates include stoichiometric hydrates as well as compositionscontaining variable amounts of water. The invention includes all suchsolvates.

The skilled artisan will further appreciate that certain compounds ofthe invention that exist in crystalline form, including the varioussolvates thereof, may exhibit polymorphism (i.e. the capacity to occurin different crystalline structures). These different crystalline formsare typically known as “polymorphs.” The invention includes all suchpolymorphs. Polymorphs have the same chemical composition but differ inpacking, geometrical arrangement, and other descriptive properties ofthe crystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability, and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra, and X-ray powder diffractionpatterns, which may be used for identification. The skilled artisan willappreciate that different polymorphs may be produced, for example, bychanging or adjusting the reaction conditions or reagents, used inmaking the compound. For example, changes in temperature, pressure, orsolvent may result in polymorphs. In addition, one polymorph mayspontaneously convert to another polymorph under certain conditions.

The compound of Formula (I) or a salt thereof may exist instereoisomeric forms (e.g., it contains one or more asymmetric carbonatoms). The individual stereoisomers (enantiomers and diastereomers) andmixtures of these are included within the scope of the presentinvention. Likewise, it is understood that a compound or salt of Formula(I) may exist in tautomeric forms other than that shown in the formulaand these are also included within the scope of the present invention.It is to be understood that the present invention includes allcombinations and subsets of the particular groups defined hereinabove.The scope of the present invention includes mixtures of stereoisomers aswell as purified enantiomers or enantiomerically/diastereomericallyenriched mixtures. It is to be understood that the present inventionincludes all combinations and subsets of the particular groups definedhereinabove.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in Formula (I) and following, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention and pharmaceutically acceptable saltsthereof include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulphur, fluorine, iodine, and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable saltsof said compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.¹¹C and ¹⁸F isotopes are particularly useful in PET (positron emissiontomography), and ¹²⁵I isotopes are particularly useful in SPECT (singlephoton emission computerized tomography), all useful in brain imaging.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of Formula (I) and following of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labelled reagent for a non-isotopicallylabelled reagent.

DEFINITIONS

Terms are used within their accepted meanings. The following definitionsare meant to clarify, but not limit, the terms defined.

As used herein, the term “alkyl” represents a saturated, straight orbranched hydrocarbon moiety having the specified number of carbon atoms.The term “(C₁-C₄)alkyl” refers to an alkyl moiety containing from 1 to 4carbon atoms. Exemplary alkyls include, but are not limited to methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, and t-butyl.

When the term “alkyl” is used in combination with other substituentgroups, such as “halo(C₁-C₄)alkyl” or “hydroxy(C₁-C₄)alkyl”, the term“alkyl” is intended to encompass a divalent straight or branched-chainhydrocarbon radical, wherein the point of attachment is through thealkyl moiety. “halo(C₁-C₄)alkyl” is intended to mean a radical havingone or more halogen atoms, which may be the same or different, at one ormore carbon atoms of an alkyl moiety containing from 1 to 4 carbonatoms, which is a straight or branched-chain carbon radical. Examples of“halo(C₁-C₄)alkyl” groups useful in the present invention include, butare not limited to, —CHF₂ (difluoromethyl), —CF₃ (trifluoromethyl),—CCl₃ (trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl, andhexafluoroisopropyl. Examples of “hydroxy(C₁-C₄)alkyl” groups useful inthe present invention include, but are not limited to, hydroxymethyl,hydroxyethyl, and hydroxyisopropyl.

As used herein, the term “cycloalkyl” refers to a non-aromatic,saturated, cyclic hydrocarbon ring containing the specified number ofcarbon atoms. The term “(C₃-C₇)cycloalkyl” refers to a non-aromaticcyclic hydrocarbon ring having from three to seven ring carbon atoms.Exemplary “(C₃-C₇)cycloalkyl” groups useful in the present inventioninclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

“Alkoxy” refers to a group containing an alkyl radical, definedhereinabove, attached through an oxygen linking atom. The term“(C₁-C₄)alkoxy” refers to a straight- or branched-chain hydrocarbonradical having at least 1 and up to 4 carbon atoms attached through anoxygen linking atom. Exemplary “(C₁-C₄)alkoxy” groups useful in thepresent invention include, but are not limited to, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and t-butoxy.

The term “halo(C₁-C₄)alkoxy” refers to a straight- or branched-chainhydrocarbon radical, having at least 1 and up to 4 carbon atoms with oneor more halogen atoms, which may be the same or different, attached toone or more carbon atoms, which radical is attached through an oxygenlinking atom. Exemplary “halo(C₁-C₄)alkoxy” groups useful in the presentinvention include, but are not limited to, —OCHF₂ (difluoromethoxy),—OCF₃ (trifluoromethoxy), and —OCH(CF₃)₂(hexafluoroisopropoxy).

“Cycloalkoxy” refers to a group containing a cycloalkyl radical, definedhereinabove, attached through an oxygen linking atom. The term“(C₃-C₇)cycloalkoxy” refers to a non-aromatic, saturated, cyclichydrocarbon ring having from three to seven ring carbon atoms attachedthrough an oxygen linking atom. Exemplary “(C₃-C₇)cycloalkoxy” groupsuseful in the present invention include, but are not limited to,cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, andcycloheptyloxy.

As used herein, “halogen” or “halo” refers to F, Cl, Br, or I. “Oxo”represents a double-bonded oxygen moiety; for example, if attacheddirectly to a carbon atom forms a carbonyl moiety (C═O). “Hydroxy” or“hydroxyl” is intended to mean the radical —OH. As used herein, the term“cyano” refers to the group —CN.

As used herein, “4- to 6-membered heterocycloalkyl” represents a groupor moiety comprising a non aromatic, monovalent monocyclic radical,which is saturated or partially unsaturated, containing 4, 5, or 6 ringatoms, which includes one or two heteroatoms selected independently fromoxygen, sulfur, and nitrogen. Illustrative examples of 4- to 6-memberedheterocycloalkyl groups useful in the present invention include, but arenot limited to azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl,pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl,tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl,1,3-oxathianyl, and 1,3-dithianyl.

As used herein, “5- or 6-membered heteroaryl” represents a group ormoiety comprising an aromatic monovalent monocyclic radical, containing5 or 6 ring atoms, including at least one carbon atom and 1 to 4heteroatoms independently selected from nitrogen, oxygen and sulfur.Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, orsulfur ring heteroatom, and optionally contain 1, 2, or 3 additionalnitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2,or 3 nitrogen ring heteroatoms. Illustrative examples of 5- or6-membered heteroaryl groups useful in the present invention include,but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, and triazinyl.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur and event(s) that do not occur.

The term “independently” means that where more than one substituent isselected from a number of possible substituents, those substituents maybe the same or different. The alternative definitions for the variousgroups and substituent groups of Formula (I) provided throughout thespecification are intended to particularly describe each compoundspecies disclosed herein, individually, as well as groups of one or morecompound species. The scope of this invention includes any combinationof these group and substituent group definitions.

PHARMACEUTICAL COMPOSITIONS

The invention further provides a pharmaceutical composition (alsoreferred to as pharmaceutical formulation) comprising a compound ofFormula (I) or a pharmaceutically acceptable salt thereof, and one ormore excipients (also referred to as carriers and/or diluents in thepharmaceutical arts). The excipients are pharmaceutically acceptable inthe sense of being compatible with the other ingredients of theformulation and not deleterious to the recipient thereof (i.e., thepatient).

In accordance with another aspect of the invention there is provided aprocess for the preparation of a pharmaceutical composition comprisingmixing (or admixing) a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof, with at least one excipient.

Pharmaceutical compositions may be in unit dose form containing apredetermined amount of active ingredient per unit dose. Such a unit maycontain a therapeutically effective dose of the compound of Formula (I)or a pharmaceutically acceptable salt thereof, or a fraction of atherapeutically effective dose such that multiple unit dosage formsmight be administered at a given time to achieve the desiredtherapeutically effective dose. Preferred unit dosage formulations arethose containing a daily dose or sub-dose, as herein above recited, oran appropriate fraction thereof, of an active ingredient. Furthermore,such pharmaceutical compositions may be prepared by any of the methodswell-known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example, by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual, ortransdermal), vaginal, or parenteral (including subcutaneous,intramuscular, intravenous, or intradermal) routes. Such compositionsmay be prepared by any method known in the art of pharmacy, for example,by bringing into association the active ingredient with theexcipient(s).

When adapted for oral administration, pharmaceutical compositions may bein discrete units such as tablets or capsules, powders or granules,solutions or suspensions in aqueous or non-aqueous liquids, edible foamsor whips, oil-in-water liquid emulsions or water-in-oil liquidemulsions. The compound or salt thereof of the invention or thepharmaceutical composition of the invention may also be incorporatedinto a candy, a wafer, and/or tongue tape formulation for administrationas a “quick-dissolve” medicine.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders or granules are prepared bycomminuting the compound to a suitable fine size and mixing with asimilarly comminuted pharmaceutical carrier such as an ediblecarbohydrate, as, for example, starch or mannitol. Flavoring,preservative, dispersing, and coloring agents can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin or non-gelatinous sheaths. Glidants andlubricants such as colloidal silica, talc, magnesium stearate, calciumstearate, solid polyethylene glycol can be added to the powder mixturebefore the filling operation. A disintegrating or solubilizing agentsuch as agar-agar, calcium carbonate, or sodium carbonate can also beadded to improve the availability of the medicine when the capsule isingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugars,such as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth, sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, andaliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt, and/oran absorption agent such as bentonite, kaolin, or dicalcium phosphate.The powder mixture can be granulated by wetting a binder such as asyrup, starch paste, acadia mucilage, or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through a tablet machine,resulting in imperfectly formed slugs broken into granules. The granulescan be lubricated to prevent sticking to the tablet forming dies bymeans of the addition of stearic acid, a stearate salt, talc, or mineraloil. The lubricated mixture is then compressed into tablets. Thecompound or salt of the present invention can also be combined with afree-flowing inert carrier and compressed into tablets directly withoutgoing through the granulating or slugging steps. A clear opaqueprotective coating consisting of a sealing coat of shellac, a coating ofsugar, or polymeric material, and a polish coating of wax can beprovided. Dyestuffs can be added to these coatings to distinguishdifferent dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of active ingredient. Syrups can be prepared by dissolving thecompound or salt thereof of the invention in a suitably flavouredaqueous solution, while elixirs are prepared through the use of anon-toxic alcoholic vehicle. Suspensions can be formulated by dispersingthe compound or salt of the invention in a non-toxic vehicle.Solubilizers and emulsifiers, such as ethoxylated isostearyl alcoholsand polyoxyethylene sorbitol ethers, preservatives, flavor additivessuch as peppermint oil, natural sweeteners, saccharin, or otherartificial sweeteners, and the like, can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as, for example, by coating or embedding particulatematerial in polymers, wax, or the like.

In the present invention, tablets and capsules are preferred fordelivery of the pharmaceutical composition.

As used herein, the term “treatment” refers to alleviating the specifiedcondition, eliminating or reducing one or more symptoms of thecondition, slowing or eliminating the progression of the condition, andpreventing or delaying the reoccurrence of the condition in a previouslyafflicted or diagnosed patient or subject.

The present invention provides a method of treatment in a mammal,especially a human, suffering from obesity, diabetes, hypertension,depression, anxiety, drug addiction, substance addiction, or acombination thereof. Such treatment comprises the step of administeringa therapeutically effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof, to said mammal, particularly ahuman. Treatment can also comprise the step of administering atherapeutically effective amount of a pharmaceutical compositioncontaining a compound of Formula (I) or a pharmaceutically acceptablesalt thereof, to said mammal, particularly a human.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought, forinstance, by a researcher or clinician.

The term “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount,results in improved treatment, healing, prevention, or amelioration of adisease, disorder, or side effect, or a decrease in the rate ofadvancement of a disease or disorder. The term also includes within itsscope amounts effective to enhance normal physiological function. Foruse in therapy, therapeutically effective amounts of a compound ofFormula (I), as well as salts thereof, may be administered as the rawchemical. Additionally, the active ingredient may be presented as apharmaceutical composition. While it is possible that, for use intherapy, a therapeutically effective amount of a compound of Formula (I)or a pharmaceutically acceptable salt thereof, may be administered asthe raw chemical, it is typically presented as the active ingredient ofa pharmaceutical composition or formulation.

The precise therapeutically effective amount of a compound or saltthereof of the invention will depend on a number of factors, including,but not limited to, the age and weight of the subject (patient) beingtreated, the precise disorder requiring treatment and its severity, thenature of the pharmaceutical formulation/composition, and route ofadministration, and will ultimately be at the discretion of theattending physician or veterinarian. Typically, a compound of Formula(I) or a pharmaceutically acceptable salt thereof, will be given for thetreatment in the range of about 0.1 to 100 mg/kg body weight ofrecipient (patient, mammal) per day and more usually in the range of 0.1to 10 mg/kg body weight per day. Acceptable daily dosages may be fromabout 0.1 to about 1000 mg/day, and preferably from about 1 to about 100mg/day. This amount may be given in a single dose per day or in a number(such as two, three, four, five, or more) of sub-doses per day such thatthe total daily dose is the same. An effective amount of a salt thereofmay be determined as a proportion of the effective amount of thecompound of Formula (I) per se. Similar dosages should be appropriatefor treatment of the other conditions referred herein for treatment. Ingeneral, determination of appropriate dosing can be readily arrived atby one skilled in medicine or the pharmacy art.

Additionally, the present invention provides the use of a compound ofthe invention in combination with weight management therapies or othertriglyceride lowering therapy. In particular, the present inventionprovides a combination of a compound of Formula (I) or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof with at least one other therapeutically activeagent, including another anti-obesity drug and/or an anti-diabetes drug.Such other therapeutically active agent can include, for example,metformin (Glucophage®), CB1 receptor antagonists, GLP-1 agonists,opioid antagonists, and neurotransmitter reuptake inhibitors. When acompound of the invention is employed in combination with anotheranti-obesity drug or anti-diabetes drug, it is to be appreciated bythose skilled in the art that the dose of each compound or drug of thecombination may differ from that when the drug or compound is usedalone. Appropriate doses will be readily appreciated and determined bythose skilled in the art. The appropriate dose of the compound ofFormula (I) or a pharmaceutically acceptable salt thereof, and the othertherapeutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect, and are within the expertise and discretion of theattending doctor or clinician.

Compounds Preparation Generic Synthesis Schemes

The compounds of this invention may be made by a variety of methods,including well-known standard synthetic methods. Illustrative generalsynthetic methods are set out below and then specific compounds of theinvention are prepared in the working examples. The skilled artisan willappreciate that if a substituent described herein is not compatible withthe synthetic methods described herein, the substituent may be protectedwith a suitable protecting group that is stable to the reactionconditions. The protecting group may be removed at a suitable point inthe reaction sequence to provide a desired intermediate or targetcompound. In all of the schemes described below, protecting groups forsensitive or reactive groups are employed where necessary in accordancewith general principles of synthetic chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Green and P. G. M. Wuts, (1991) Protecting Groups in Organic Synthesis,John Wiley & Sons, incorporated by reference with regard to protectinggroups). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection of processes as well as the reaction conditionsand order of their execution shall be consistent with the preparation ofcompounds of the present invention.

The synthesis of the compounds of the general Formula (I) andpharmaceutically acceptable derivatives and salts thereof may beaccomplished as outlined below in Schemes 1-5 by those skilled in theart. In the following description, the groups are as defined above forcompounds of Formula (I) unless otherwise indicated. Starting materialsare commercially available or are made from commercially availablematerials using methods known to those skilled in the art.

Compounds of Formula (I) may be prepared as illustrated in Scheme 1. Anappropriately substituted 5-bromo indole or azaindole derivative A canbe treated with an aptly substituted alkyl (or cycloalkyl orheterocycloalkyl) or a phenyl (or heteroaryl) coupling precursor such asa bromide, iodide, or triflate under suitable conditions to effect thecorresponding alkylation or arylation to afford the indole or azaindolederivative B. Indole or azaindole B can be subjected to amination underBuchwald conditions using an appropriately protected ethanolamine in thepresence of reagents such as palladium acetate, a ligand such as X-Phos,and a base such as cesium carbonate in toluene at 110° C. Intermediate Cthus obtained can then be coupled to 4,6-dichloropyrimidine-5-carbonylchloride to afford D. Desilylation of intermediate D under standard TBAFconditions leads to E which is then subjected to ring closure by heatingthe reaction mixture in acetonitrile at 80° C. in the presence of a basesuch as triethylamine to give F. Substitution of the chloro residue inintermediate F with an amino group by treatment with ammonia at roomtemperature results in compounds of Formula (I) (1a).

Compounds of Formula (I) may also be prepared as illustrated in Scheme2. An appropriately substituted 5-bromo indole or azaindole derivative Acan be treated with 1-(benzyloxy)-2-bromobenzene to effect thecorresponding arylation affording compound G. Compound G can besubjected to amination under Buchwald conditions using an appropriatelyprotected ethanolamine in the presence of reagents such as palladiumacetate, a ligand such as X-Phos, and a base such as cesium carbonate intoluene at 110° C. Intermediate H thus obtained can then be coupled to4,6-dichloropyrimidine-5-carbonyl chloride to afford I. Desilylation ofintermediate I under standard TBAF conditions leads to J which is thensubjected to ring closure by heating the reaction mixture inacetonitrile at 80° C. in the presence of a base such as triethylamineto give K. Substitution of the chloro residue in intermediate K with anamino group by treatment with ammonia at room temperature results in theamino pyrimidine L. The masked phenol in L is then revealed underpalladium on carbon catalyzed hydrogenolysis conditions to give thephenol M which now can be alkylated with suitable alkyl bromides R—Brunder standard conditions to give compounds of Formula (I) (1b).

Compounds of Formula (I) may also be synthesized as illustrated inScheme 3. An appropriately substituted 5-bromo indole or azaindolederivative A is treated first with phosgene at 0° C. to convert it intoa reactive acyl intermediate which then is treated with a suitablysubstituted acyl hydrazine in the presence of triethylamine at roomtemperature to afford the diacyl hydrazine N. The conversion of N tooxadiazole derivative O can be achieved by treatment with POCl₃ inrefluxing toluene. Aryl bromide O can be subjected to amination underBuchwald conditions using an appropriately protected ethanolamine in thepresence of reagents such as palladium acetate, a ligand such as X-Phos,and a base such as cesium carbonate in toluene at 110° C. Intermediate Pthus obtained can then be coupled to 4,6-dichloropyrimidine-5-carbonylchloride to afford Q. Desilylation of intermediate Q under standardacidic conditions leads to R which is then subjected to ring closure byheating the reaction mixture in acetonitrile at 80° C. in the presenceof a base such as triethylamine to give S. Substitution of the chlororesidue in intermediate S with an amino group by treatment with ammoniaat room temperature results in compounds of Formula (I) (1c).

Compounds of Formula (I) may also be synthesized as illustrated inScheme 4. The nitro indoline derivative T is brominated in the firststep using bromine in acetic acid to afford the meta-brominated productU. Indoline U is now oxidized to the more stable indole V which is thenalkylated (or arylated accordingly) with an appropriate bromide reagentR¹—Br in the presence of cesium carbonate and DMF to give indole W. Thebromine in W can now undergo coupling reaction with an appropriateboronic acid (or boronate ester) under standard Suzuki conditions (or anamine under Buchwald conditions) to give 7-substituted indole derivativeAA. The nitro group is reduced to the corresponding amine byhydrogenolysis in the presence of palladium on carbon to afford AB.Aniline AB can then be alkylated with a suitably substituted bromideunder heating conditions to afford intermediate C which can be convertedto compounds of Formula (I) (1d) as described in Scheme 1.

Compounds of Formula (I) may also be synthesized as illustrated inScheme 5. Indole AC can be acylated by treatment with an appropriateacid chloride R″COCl to give indole AD. N-Alkylation or arylationprovides intermediate AE. Coupling of bromoindole AE with anappropriately protected ethanolamine under standard Buchwald conditionsgives indole derivative AF. Intermediate AF can be converted tocompounds of Formula (I) (le) as described in Scheme 1.

EXPERIMENTALS

The following examples illustrate the invention. These examples are notintended to limit the scope of the present invention, but rather toprovide guidance to the skilled artisan to prepare and use thecompounds, compositions, and methods of the present invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention. Unless otherwise noted, reagents are commercially availableor are prepared according to procedures in the literature. The symbolsand conventions used in the descriptions of processes, schemes, andexamples are consistent with those used in the contemporary scientificliterature, for example, the Journal of the American Chemical Society orthe Journal of Biological Chemistry.

In the Examples:

Chemical shifts are expressed in parts per million (ppm) units. Couplingconstants (J) are in units of hertz (Hz). Splitting patterns describeapparent multiplicities and are designated as s (singlet), d (doublet),t (triplet), q (quartet), dd (double doublet), dt (double triplet), m(multiplet), br (broad).

Flash column chromatography was performed on silica gel.

The naming program used is ChemDraw®.

ABBREVIATIONS

Ac acetylACN acetonitrileAcOH acetic acidCs₂CO₃ cesium carbonateDCE dichloroethaneDCM dichloromethaneDDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinoneDMF dimethylformamideDMSO dimethylsulfoxideEt₃N triethylamineEtOH ethanolg gram(s)h hour(s)m/z mass to charge ratioMeOH methanolmmol millimolesNMR nuclear magnetic resonanceOxz oxazepinonesPd palladiumPd/C palladium on carbonPd(Cl₂)dppf [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II)Pd(OAc)₂ palladium acetatePy pyridinert room temperatureTBAF tetrabutylammonium fluorideTBDMS (TBS) tert-butyldimethylsilylTf₂O trifluoromethanesulfonic anhydrideTFA trifluoroacetic acidTFAA trifluoroacetic anhydrideTHF tetrahydrofuranX-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Example 1

Procedures4-Amino-6-(1-(oxetan-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one5-Bromo-1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine (1A)

Oxetan-3-yl methanesulfonate (1.397 g, 9.18 mmol) was added to asolution of 5-bromo-1H-indole (1.5 g, 7.65 mmol) in DMF (15 mL) followedby cesium carbonate (3.74 g, 11.48 mmol), and the mixture was stirred at70° C. for 1 h. Insoluble solids were filtered, the filtrate wasconcentrated and the residue was partitioned between ethyl acetate andwater. Separated organic layer was dried over sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure andpurified by flash chromatography using 5% ethyl acetate in hexanes toafford the title compound (0.6 g, 30.5%) as an oil. ¹H NMR (400 MHz,CDCl₃): δ 7.77 (d, J=1.6 Hz, 1H), 7.42 (d, J=3.2 Hz, 1H), 7.35 (d, J=8.8Hz, 1H), 7.30 (dd, J₁=2.0 Hz, J₂=8.8 Hz, 1H), 6.54 (d, J=2.8 Hz, 1H),5.58-5.45 (m, 1H), 5.17 (t, J=7.2 Hz, 2H), 5.05 (t, J=6.8 Hz, 2H).ESI-MS m/z=252 (M+H)⁺.

N-(2-(tert-Butyldimethylsilyloxy)ethyl)-1-(oxetan-3-yl)-1H-indol-5-amine(1B)

A mixture of Example 1A (0.6 g, 2.38 mmol),2-(tert-butyldimethylsilyloxy)ethanamine (0.501 g, 2.86 mmol), cesiumcarbonate (1.163 g, 3.57 mmol), palladium acetate (0.0534 g, 0.238 mmol)and X-Phos (0.113 g, 0.238 mmol) in toluene (20 mL) was refluxed at 110°C. under argon for 12 h. The reaction mixture was cooled, diluted withethyl acetate, washed with water (2×20 mL). The separated organic layerwas dried over sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and purified by flash chromatography using 10%ethyl acetate in hexanes to afford the title compound (0.45 g, 33%) asan oil. ¹H NMR (400 MHz, CDCl₃): δ 7.40 (d, J=3.2 Hz, 1H), 7.34-7.30 (m,2H), 7.02-6.87 (m, 1H), 6.43 (d, J=2.4 Hz, 1H), 5.49 (m, 1H), 5.13 (t,J=6.8 Hz, 2H), 5.05 (t, J=6.8 Hz, 2H), 3.84 (t, J=5.6 Hz, 2H), 3.27 (t,J=5.2 Hz, 2H), 0.89 (s, 9H), 0.06 (s, 6H). ESI-MS m/z=347 (M+H)⁺.

N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-(oxetan-3-yl)-1H-indol-5-yl)pyrimidine-5-carboxamide(1C)

A solution of 4,6-dichloropyrimidine-5-carbonyl chloride (0.276 g, 1.558mmol) in DCM (5 mL) was added dropwise to an ice-cold solution ofExample 1B (0.45 g, 1.299 mmol) and triethylamine (0.543 mL, 3.90 mmol)in DCM (20 mL) and the mixture was stirred for 1 h. The reaction mixturewas concentrated in vacuo, and the residue was partitioned between ethylacetate and water. The separated organic layer was dried over sodiumsulphate and filtered. The filtrate was concentrated in vacuo andpurified by flash chromatography using 15% ethyl acetate in hexanes toafford the title compound (0.45 g, 62%) as a yellow solid. ¹H NMR (400MHz, CDCl₃): δ 8.46 (s, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.43 (d, J=3.2 Hz,1H), 7.27 (d, J=8.8 Hz, 1H), 7.23 (m, 1H), 6.50 (d, J=6.8 Hz, 1H), 5.47(m, 1H), 5.12 (t, J=7.2 Hz, 2H), 4.97 (t, J=6.8 Hz, 2H), 4.03 (t, J=5.6Hz, 2H), 3.89 (t, J=5.6 Hz, 2H), 0.85 (s, 9H), 0.05 (s, 6H). ESI-MSm/z=521 (M+H)⁺.

4,6-Dichloro-N-(2-hydroxyethyl)-N-(1-(oxetan-3-yl)-1H-indol-5-yl)pyrimidine-5-carboxamide(1D)

TBAF (0.301 g, 1.151 mmol) in THF (10 mL) was added to a solution ofExample 1C (0.3 g, 0.575 mmol) in THF (5 mL) and stirred at roomtemperature for 2 h. THF was removed in vacuo, and the residue waspartitioned between ethyl acetate and water. The separated organic layerwas dried over sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to afford the title compound (0.21 g, 46%) as asolid. ¹H NMR (400 MHz, CDCl₃): δ 8.49 (s, 1H), 7.69 (d, J=1.2 Hz, 1H),7.46 (m, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.23 (dd, J₁=2.0 Hz, J₂=10.4 Hz,1H), 6.55 (d, J=3.6 Hz, 1H), 5.49 (m, 1H), 5.14 (t, J=8.0 Hz, 2H), 4.99(t, J=6.8 Hz, 2H), 4.14 (t, J=5.2 Hz, 2H), 3.93 (t, J=5.2 Hz, 2H).ESI-MS m/z=407 (M+H)⁺.

4-Chloro-6-(1-(oxetan-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(1E)

A slurry of Example 1D (0.21 g, 0.516 mmol) and triethylamine (0.216 mL,1.547 mmol) in acetonitrile (8 mL) was stirred at 80° C. for 6 h. Thereaction mixture was cooled, concentrated in vacuo and partitionedbetween ethyl acetate and water. The separated organic layer was driedover sodium sulfate and filtered, and the filtrate was concentrated invacuo to afford the title compound (0.16 g, 73%) as a white solid. ¹HNMR (400 MHz, CDCl₃): δ 8.77 (s, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.58 (d,J=9.2 Hz, 1H), 7.48 (d, J=2.8 Hz, 1H), 7.22 (dd, J=1.6 Hz, J₂=8.8 Hz,1H), 6.64 (d, J=3.6 Hz, 1H), 5.57 (m, 1H), 5.20 (t, J=7.2 Hz, 2H), 5.07(t, J=6.8 Hz, 2H), 4.80 (t, J=4.8 Hz, 2H), 4.08 (t, J=5.2 Hz, 2H).ESI-MS m/z=371 (M+H)⁺.

4-Amino-6-(1-(oxetan-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(1)

A solution of Example 1E (0.15 g, 0.405 mmol), in 0.5M ammonia in1,4-dioxane (8 mL) was stirred at room temperature for 2 h. The reactionmixture was concentrated in vacuo and partitioned between ethyl acetateand water. Separated organic layer was dried over sodium sulfate andfiltered. The filtrate was concentrated in reduced pressure to affordthe title compound (0.08 g, 52.3%) as an off-white solid. ¹H NMR (300MHz, DMSO-d₆): δ 8.17 (s, 1H), 7.81 (d, J=3.3 Hz, 1H), 7.65-7.58 (m,3H), 7.55 (d, J=1.8 Hz, 1H), 7.13 (dd, J₁=1.8 Hz, J₂=9.0 Hz, 1H), 6.58(d, J=3.0 Hz, 1H), 5.78 (m, 1H), 5.06 (t, J=7.5 Hz, 2H), 4.93 (t, J=6.6Hz, 2H), 4.64 (t, J=4.5 Hz, 2H), 3.98 (t, J=4.5 Hz, 2H). ESI-MS m/z=352(M+H)⁺; HPLC purity: 94%.

Example 2

Procedures4-Amino-6-(1-(3-(trifluoromethoxy)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one5-Bromo-1-(3-(trifluoromethoxy)phenyl)-1H-indole (2A)

1-Iodo-3-(trifluoromethyl)benzene (2.204 g, 7.65 mmol) was added to asolution of 5-bromo-1H-indole (1.5 g, 7.65 mmol) and copper(I) bromide(0.110 g, 0.765 mmol) in DMF (30 mL) followed by potassium carbonate(2.115 g, 15.30 mmol) and the mixture was stirred at 100° C. for 10 min.NaOH (0.0131 g, 0.765 mmol) and copper(II) acetate (0.138 g, 0.765 mmol)were then added at 110° C., and the reaction mixture was stirred for 16h. Insoluble solids were filtered, the filtrate was concentrated, andthe residue was partitioned between ethyl acetate and water. Theseparated organic layer was dried over sodium sulphate and filtered, andthe filtrate was concentrated in vacuo to afford the title compound (0.8g, 29%), which was carried on to the next step without any furtherpurification. ESI-MS m/z=356 (M+H)⁺.

N-(2-(tert-Butyldimethylsilyloxy)ethyl)-1-(3-(trifluoromethoxy)phenyl)-1H-indol-5-amine(2B)

A mixture of Example 2A (0.8 g, 2.246 mmol),2-(tert-butyldimethylsilyloxy)ethanamine (0.394 g, 2.246 mmol), cesiumcarbonate (1.098 g, 3.37 mmol), palladium acetate (50.4 mg, 0.225 mmol)and X-Phos (0.107 g, 0.225 mmol) in toluene (20 mL) under argon wasrefluxed at 110° C. for 4 h. The reaction mixture was warmed to roomtemperature and partitioned between ethyl acetate and water. Theseparated organic layer was dried over sodium sulfate and filtered. Thefiltrate was concentrated in vacuo and purified by flash chromatographyusing 10% ethyl acetate in hexanes to afford the title compound (0.4 g,39.5%) as a syrup. ¹H NMR (400 MHz, CDCl₃): δ 7.50 (t, J=8.0 Hz, 1H),7.44 (d, J=2.4 Hz, 1H), 7.41-7.36 (m, 2H), 7.24 (d, J=3.6 Hz, 1H), 7.15(d, J=7.6 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.68 (dd, J₁=1.6 Hz, J₂=8.8Hz, 1H), 6.54 (d, J=3.2 Hz, 1H), 3.97 (bs, 1H), 3.86 (t, J=5.6 Hz, 2H),3.27 (t, J=5.2 Hz, 2H), 0.94 (s, 9H), 0.07 (s, 6H). ESI-MS m/z=451(M+H)⁺.

N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-(3-(trifluoromethoxy)phenyl)-1H-indol-5-yl)pyrimidine-5-carboxamide(2C)

A solution of 4,6-dichloropyrimidine-5-carbonyl chloride (0.188 g, 0.888mmol) in DCM (5 mL) was added dropwise to an ice-cold solution ofExample 2B (0.4 g, 0.888 mmol) and triethyl amine (0.188 mL, 3.55 mmol)in DCM (25 mL), and the reaction mixture was stirred for 2 h. This wasthen concentrated in vacuo, and the residue was partitioned betweenethyl acetate and water. The separated organic layer was dried oversodium sulphate and filtered. The filtrate was concentrated in vacuo andpurified by flash chromatography using 12% ethyl acetate in hexane toafford the title compound (0.3 g, 54%) as a syrup. ¹H NMR (400 MHz,CDCl₃): δ 8.50 (s, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H),738-7.30 (m, 5H), 7.22 (s, 1H), 6.62 (d, J=2.8 Hz, 1H), 4.06 (t, J=6.0Hz, 2H), 3.93 (t, J=5.6 Hz, 2H), 0.88 (s, 9H), 0.07 (s, 6H). ESI-MSm/z=626 (M+H)⁺.

4,6-Dichloro-N-(2-hydroxyethyl)-N-(1-(3-(trifluoromethoxy)phenyl)-1H-indol-5-yl)pyrimidine-5-carboxamide(2D)

HCl (0.12 mL, 3.29 mmol) was added to a solution of Example 2C (0.3 g,0.480 mmol) in methanol (15 mL), and the mixture was stirred at roomtemperature for 1 h. Methanol was removed in vacuo, the residuedissolved in ethyl acetate, washed with saturated aqueous sodiumbicarbonate and saturated aqueous brine. The separated organic layer wasdried over sodium sulfate and filtered, and the filtrate wasconcentrated in vacuo to afford the title compound (0.2 g, 82%) as asolid, which was carried on to the next step without furtherpurification. ESI-MS m/z=511 (M+H)⁺.

4-Chloro-6-(1-(3-(trifluoromethoxy)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(2E)

A slurry of Example 2D (0.2 g, 0.391 mmol) and triethylamine (0.156 mL,1.565 mmol) in acetonitrile (20 mL) was stirred at 90° C. for 12 h. Thereaction mixture was cooled and concentrated in vacuo, and the residuewas partitioned between ethyl acetate and water. The separated organiclayer was dried over sodium sulfate and filtered, and the filtrate wasconcentrated in vacuo to afford the title compound (0.15 g, 81%) as awhite solid. ¹H NMR (300 MHz, CDCl₃): δ 8.77 (s, 1H), 7.68 (d, J=1.8 Hz,1H), 7.62-7.55 (m, 3H), 7.46-7.44 (m, 1H), 7.40-7.38 (m, 2H), 7.23 (d,J=2.4 Hz, 1H), 6.75 (d, J=3.3 Hz, 1H), 4.82 (t, J=4.8 Hz, 2H), 4.10 (t,J=4.8 Hz, 2H). ESI-MS m/z=475 (M+H)⁺.

4-Amino-6-(1-(3-(trifluoromethoxy)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(2)

A solution of Example 2E (0.15 g, 0.316 mmol) in 0.5 M ammonia in1,4-dioxane (10 mL) was stirred at room temperature for 2 h. Thereaction mixture was concentrated in vacuo, the residue was partitionedbetween ethyl acetate and water. Separated organic layer was dried oversodium sulfate and filtered. The filtrate was concentrated under reducedpressure to afford the title compound (0.095 g, 59%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 8.14 (s, 1H), 7.76 (d, J=3.6 Hz, 1H),7.72-7.57 (m, 7H), 7.39 (d, J=8.0 Hz, 1H), 7.17 (dd, J₁=2.0 Hz, J₂=8.8Hz, 1H), 6.74 (d, J=2.8 Hz, 1H), 4.62 (t, J=4.4 Hz, 2H), 3.97 (t, J=4.4Hz, 2H). ESI-MS m/z=456 (M+H)⁺; LCMS purity: 91%.

Examples 3-12 were prepared using procedures analogous to thosedescribed in Examples 1-2 with appropriate starting materials.

Exp Structure Analytical Data Mass/Purity 3

¹H NMR (300 MHz, DMSO- d₆): δ 8.22 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H),7.96 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 3.3 Hz, 1H), 7.64 (bs, 2H), 6.53(d, J = 3.6 Hz, 1H), 5.29 (m, 1H), 4.67 (t, J = 4.5 Hz, 2H), 4.01 (t, J= 4.8 Hz, 2H), 2.62- 2.35 (m, 4H), 1.91-1.80 (m, 2H). ESI-MS m/z = 351(M + H)⁺; HPLC purity: 93%. 4

¹H NMR (400 MHz, DMSO- d₆): δ 8.17 (s, 1H), 7.60 (bs, 2H), 7.57 (d, J =8.8 Hz, 1H), 7.47 (s, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 8.4Hz, 1H), 6.44 (s, 1H), 4.64 (m, 3H), 4.08 (s, 2H), 3.98 (m, 2H), 1.09(s, 6H). ESI-MS m/z = 368 (M + H)⁺; HPLC purity: 96.9%. 5

¹H NMR (400 MHz, DMSO- d₆): δ 8.14 (s, 1H), 7.67-7.60 (m, 7H), 7.55 (d,J = 2.8 Hz, 1H), 7.14-7.10 (m, 2H), 6.72 (d, J = 3.2 Hz, 1H), 4.61 (t, J= 4.0 Hz, 2H), 3.98 (t, J = 4.4 Hz, 2H). ESI-MS m/z = 456 (M + H)⁺; HPLCpurity: 94%. 6

¹H NMR (400 MHz, DMSO- d₆): δ 8.18 (s, 1H), 7.68-7.58 (m, 5H), 7.56 (d,J = 2.8 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H),7.12 (dd, J₁ = 8.8 Hz, J₂ = 2.0 Hz, 1H), 6.71 (d, J = 2.8 Hz, 1H), 4.65(t, J = 4.8 Hz, 2H), 3.99 (t, J = 4.4 Hz, 2H), 3.89 (s, 3H). ESI-MS m/z= 470 (M + H)⁺; LCMS purity: 93.7%. 7

¹H NMR (400 MHz, DMSO- d₆): δ 8.18 (s, 1H), 7.77 (d, J = 3.6 Hz, 1H),7.70-7.59 (m, 5H), 7.52 (dd, J₁ = 1.6 Hz, J₂ = 8.4 Hz, 1H), 7.43 (t, J =2.0 Hz, 1H), 7.40 (s, 1H), 7.22 (dt, J₁ = 2.0 Hz, J₂ = 8.4 Hz, 2H), 6.75(d, J = 3.2 Hz, 1H), 4.65 (t, J = 4.4 Hz, 2H), 4.01 (t, J = 4.4 Hz, 2H).ESI-MS m/z = 438 (M + H)⁺; HPLC purity: 96%. 8

¹H NMR (300 MHz, DMSO- d₆): δ 8.18 (s, 1H), 7.73 (d, J = 3.0 Hz, 1H),7.7-7.6 (m, 3H), 7.48 (t, J = 8.1 Hz, 1H), 7.2-7.1 (m, 4H), 6.99 (d, J =8.4 Hz, 1H), 6.71 (d, J = 3.3 Hz, 1H), 4.64 (t, J = 4.5 Hz, 2H), 4.01(t, J = 4.5 Hz, 2H), 3.85 (d, J = 6.6 Hz, 2H), 2.05 (m, 1H), 1.01 (d, J= 6.6 Hz, 6H). ESI-MS m/z = 444 (M + H)⁺; HPLC purity: 91.6%. 9

¹H NMR (400 MHz, DMSO- d₆): δ 8.14 (s, 1H), 7.59 (bs, 2H), 7.55 (d, J =2.0 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.45- 7.35 (m, 2H), 7.27 (d, J =7.6 Hz, 1H), 7.12 (t, J = 8.8 Hz, 1H), 7.05 (m, 2H), 6.62 (d, J = 3.2Hz, 1H), 4.61 (t, J = 4.8 Hz, 2H), 4.52 (m, 1H), 3.97 (t, J = 4.4 Hz,2H), 1.10 (d, J = 6.4 Hz, 6H). ESI-MS m/z = 430 (M + H)⁺. LCMS purity:96.4%. 10 

¹H NMR (400 MHz, DMSO- d₆): δ 8.18 (s, 1H), 7.82 (d, J = 2.8 Hz, 1H),7.74 (s, 2H), 7.70-7.55 (m, 5H), 7.22 (d, J = 8.8 Hz, 1H), 6.77 (d, J =2.8 Hz, 1H), 4.65 (m, 2H), 4.01 (m, 2H). ESI-MS m/z = 440 (M + H)⁺, HPLCpurity: 94.4%. 11 

¹H NMR (300 MHz, DMSO- d₆): δ 8.42 (d, J = 2.1 Hz, 1H), 8.22-8.15 (m,5H), 7.67 (bs, 2H), 7.59 (t, J = 1.5 Hz, 1H), 6.83 (d, J = 3.6 Hz, 1H),4.70 (t, J = 4.5 Hz, 2H), 4.07 (t, J = 6.9 Hz, 2H). ESI-MS m/z = 441(M + H)⁺, HPLC purity: 97.8%. 12 

¹H NMR (300 MHz, DMSO- d₆): δ 8.18 (s, 1H), 7.86 (t, J = 5.4 Hz, 1H),7.65-7.56 (m, 6H), 7.14 (d, J₁ = 8.7 Hz, J₂ = 1.8 Hz, 1H), 7.08 (d, J =8.4 Hz, 1H), 6.75 (d, J = 3.3 Hz, 1H), 4.64 (t, J = 5.4 Hz, 2H), 4.02(t, J = 5.1 Hz, 2H). ESI-MS m/z: 440 (M + H)⁺; LCMS purity: 95%.

Example 13

Procedures4-Amino-6-(1-(2-methylpyrimidin-5-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one5-Bromo-1-(2-methylpyrimidin-5-yl)-1H-indole (13A)

5-Bromo-2-methyl pyrimidine (0.971 g, 5.61 mmol) was added to a solutionof 5-bromo-1H-indole (1 g, 5.1 mmol) and copper(I) bromide (0.073 g,0.51 mmol) in DMF (10 mL) followed by potassium carbonate (1.762 g,12.75 mmol), and the resulting mixture was stirred at 100° C. for 10min. NaOH (0.153 g, 3.83 mmol) and copper(II) acetate (0.009 g, 0.051mmol) were added at 110° C., and the reaction mixture was stirred for 16h. Insoluble solids were filtered, and the filtrate was concentrated.The residue was partitioned between ethyl acetate and water. Separatedorganic layer was dried over sodium sulphate and filtered. The filtratewas concentrated in vacuo and purified by flash chromatography using 10%ethyl acetate in hexane to afford the title compound (0.25 g, 16%) as anoff-white solid. ¹H NMR (300 MHz, CDCl₃): δ 8.81 (s, 2H), 7.83 (d, J=1.5Hz, 1H), 7.36 (dd, J₁=1.8 Hz, J₂=8.7 Hz, 1H), 7.33-7.26 (m, 2H), 6.71(d, J=3.3 Hz, 1H), 2.82 (s, 3H). ESI-MS m/z=288 (M+H)⁺.

N-(2-(tert-Butyldimethylsilyloxy)ethyl)-1-(2-methylpyrimidin-5-yl)-1H-indol-5-amine(13B)

A mixture of Example 13A (0.25 g, 0.868 mmol),2-(tert-butyldimethylsilyloxy)ethanamine (0.183 g, 1.041 mmol), cesiumcarbonate (0.424 g, 1.301 mmol), palladium acetate (0.019 g, 0.087 mmol)and X-Phos (0.0414 g, 0.087 mmol) in toluene (10 mL) under argon wasrefluxed at 110° C. for 12 h. The reaction mixture was warmed to roomtemperature and partitioned between ethyl acetate and water. Separatedorganic layer was dried over sodium sulfate and filtered. The filtratewas concentrated in vacuo and purified by flash chromatography using 15%ethyl acetate in hexane to afford the title compound (0.15 g, 32%) as apale yellow syrup. ¹H NMR (300 MHz, CDCl₃): δ 8.82 (s, 2H), 7.31 (d,J=8.7 Hz, 1H), 7.18 (d, J=3.3 Hz, 1H), 6.89 (d, J=2.1 Hz, 1H), 6.70 (dd,J₁=2.1 Hz, J₂=8.7 Hz, 1H), 6.60 (d, J=3.3 Hz, 1H), 4.0 (bs, 1H), 3.86(t, J=5.1 Hz, 2H), 3.27 (t, J=5.1 Hz, 2H), 2.81 (s, 3H), 0.92 (s, 9H),0.08 (s, 6H). ESI-MS m/z=383 (M+H)⁺.

N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-(2-methylpyrimidin-5-yl)-1H-indol-5-yl)pyrimidine-5-carboxamide(13C)

A solution of 4,6-dichloropyrimidine-5-carbonyl chloride (0.099 g, 0.47mmol) in DCM (3 mL) was added dropwise to an ice-cold solution ofExample 13B (0.15 g, 0.392 mmol) and triethylamine (0.164 mL, 1.176mmol) in DCM (8 mL), and the mixture was stirred for 4 h. The reactionmixture was concentrated in vacuo, diluted into ethyl acetate and washedwith water (2×15 mL). The separated organic layer was dried over sodiumsulphate and filtered. The filtrate was concentrated in vacuo andpurified by flash chromatography using 15% ethyl acetate in hexanes toafford the title compound (0.1 g, 36%) as a pale yellow solid. ¹H NMR(400 MHz, CDCl₃): δ 8.78 (s, 2H), 8.50 (s, 1H), 7.77 (d, J=2.0 Hz, 1H),7.31 (dd, J₁=2.0 Hz, J₂=8.8 Hz, 1H), 7.28-7.26 (m, 2H), 6.68 (d, J=3.2Hz, 1H), 4.06 (t, J=5.6 Hz, 2H), 3.93 (t, J=6.0 Hz, 2H), 2.83 (s, 3H),0.88 (s, 9H), 0.07 (s, 6H). ESI-MS m/z=557 (M+H)⁺.

4,6-Dichloro-N-(2-hydroxyethyl)-N-(1-(2-methylpyrimidin-5-yl)-1H-indol-5-yl)pyrimidine-5-carboxamide(13D)

A solution of Example 13C (0.1 g, 0.179 mmol) in 5 mL of methanolicsolution of HCl (1M) was stirred at room temperature for 2 h. Methanolwas removed in vacuo, and the residue was dissolved in ethyl acetate andwashed with saturated aqueous sodium bicarbonate and saturated aqueousbrine. The separated organic layer was dried over sodium sulfate andfiltered, and the filtrate was concentrated in vacuo to afford the titlecompound (0.07 g, 87%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 8.76(s, 2H), 8.53 (s, 1H), 7.70 (s, 1H), 7.32-7.24 (m, 3H), 6.71 (d, J=3.3Hz, 1H), 4.16 (t, J=5.1 Hz, 2H), 3.95 (t, J=5.1 Hz, 2H), 2.83 (s, 3H).ESI-MS m/z=443 (M+H)⁺.

4-Chloro-6-(1-(2-methylpyrimidin-5-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(13E)

A slurry of Example 13D (0.07 g, 0.158 mmol) and triethylamine (0.066mL, 0.474 mmol) in acetonitrile (6 mL) was stirred at 85° C. for 6 h.The reaction mixture was cooled and concentrated in vacuo, and theresidue was partitioned between ethyl acetate and water. Separatedorganic layer was dried over sodium sulfate and filtered, and thefiltrate was concentrated in vacuo to afford the title compound (0.055g, 86%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.85 (s, 2H), 8.77(s, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.35 (d, J=3.2Hz, 1H), 7.27 (dd, J₁=2.0 Hz, J₂=8.8 Hz, 1H), 6.81 (d, J=3.6 Hz, 1H),4.82 (t, J=4.4 Hz, 2H), 4.10 (t, J=4.4 Hz, 2H), 2.87 (s, 3H). ESI-MSm/z=407 (M+H)⁺.

4-Amino-6-(1-(2-methylpyrimidin-5-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(13)

A solution of Example 13E (0.055 g, 0.135 mmol) in 0.5 M ammonia in1,4-dioxane (6 mL) was stirred at room temperature for 2 h. The reactionmixture was concentrated in vacuo and partitioned between ethyl acetateand water. The separated organic layer was washed with saturated aqueousbrine, dried over sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to afford the title compound (0.035 g, 60%) as awhite solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.03 (s, 2H), 8.18 (s, 1H),7.81 (d, J=2.7 Hz, 1H), 7.68-7.58 (m, 4H), 7.21 (dd, J₁ 1.5 Hz, J₂=9.0Hz, 1H), 6.81 (d, J=3.3 Hz, 1H), 4.65 (t, J=3.9 Hz, 2H), 4.01 (t, J=3.9Hz, 2H), 2.73 (s, 3H). ESI-MS m/z=388 (M+H)⁺; HPLC purity: 98.8%.

Examples 14-15 were prepared using procedures analogous to thosedescribed in Example 13 using appropriate starting materials.

Exp Structure Analytical Data Mass/Purity 14

¹H NMR (300 MHz, DMSO-d₆): δ 8.95 (d, J = 2.7 Hz, 1H), 8.31 (d, J = 2.1Hz, 1H), 8.20 (dd, J₁ = 8.4 Hz, J₂ = 3.0 Hz, 1H), 8.16 (s, 1H), 8.10 (d,J = 2.4 Hz, 1H), 8.03 (d, J = 3.6 Hz, 1H), 7.64 (s, 2H), 7.43 (d, J =8.7 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 4.66 (t, J = 5.1 Hz, 2H), 4.03(t, J = 4.2 Hz, 2H), 2.52 (s, 3H). ESI-MS m/z = 388 (M + H)⁺; HPLCpurity: 99%. 15

¹H NMR (300 MHz, DMSO-d₆): δ 8.18 (s, 1H), 8.13 (d, J = 3.0 Hz, 1H),7.67 (d, J = 3.0 Hz, 1H), 7.66- 7.58 (m, 3H), 7.54 (d, J = 3.3 Hz, 1H),7.42 (d, J = 8.4 Hz, 1H), 7.15 (dd, J₁ = 2.1 Hz, J₂ = 8.7 Hz, 1H), 6.67(d, J = 3.0 Hz, 1H), 6.55 (d, J = 9.6 Hz, 1H), 4.65 (t, J = 4.8 Hz, 2H),3.99 (t, J = 4.5 Hz, 2H), 3.51 (s, 3H). ESI-MS m/z = 403 (M + H)⁺; HPLCpurity: 95.7%.

Examples 16 & 17

Procedures4-Amino-6-(1-(2-(cyclopentyloxy)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one1-(Benzyloxy)-2-bromobenzene (16A)

Potassium carbonate (47.9 g, 347 mmol) and benzyl bromide (21.75 g, 127mmol) were added to an ice-cold solution of 2-bromophenol (20 g, 116mmol) in DMF (200 mL), and the mixture was stirred at room temperaturefor 4 h. The reaction mixture was partitioned between ethyl acetate andwater. Separated organic layer was washed with saturated brine, driedover sodium sulphate and filtered, and the filtrate was concentrated invacuo to afford the title compound (26 g, 85%) as a syrup, which wascarried on to the next step without further purification. ¹H NMR (300MHz, DMSO-d₆): δ 7.59 (dd, J₁=7.5, J₂=1.2 Hz, 1H), 7.48 (d, J=6.6 Hz,2H), 7.43-7.31 (m, 4H), 7.18 (dd, J₁=7.2 Hz, J₂=1.2 Hz, 1H), 6.91 (dt,J₁=1.2 Hz, J₂=7.8 Hz, 1H), 5.21 (s, 2H). ESI-MS m/z=263 (M+H)⁺.

1-(2-(Benzyloxy)phenyl)-5-bromo-1H-indole (16B)

Potassium carbonate (21.15 g, 153 mmol), copper (I) bromide (1.463 g,10.2 mmol) and ethane-1,2-diamine (0.307 g, 5.1 mmol) were added to amixture of example 16A (17.45 g, 66.3 mmol) and 5-bromo-1H-indole (10 g,51.0 mmol) in DMF (80 mL), and the resulting mixture was stirred at 100°C. for 14 h. Insoluble solids were filtered, and the filtrate wasconcentrated and partitioned between ethyl acetate and water. Separatedorganic layer was dried over sodium sulphate and filtered, and thefiltrate was concentrated in vacuo. The crude product was purified byflash chromatography using 2% ethyl acetate in hexane to afford thetitle compound (4.5 g, 23%) as an off-white solid. ¹H NMR (300 MHz,DMSO-d₆): δ 7.81 (d, J=1.8 Hz, 1H), 7.54 (d, J=3.0 Hz, 1H), 7.50-7.36(m, 3H), 7.28-7.08 (m, 8H), 6.63 (d, J=3.0 Hz, 1H), 5.12 (s, 2H). ESI-MSm/z=378 (M+H)⁺.

1-(2-(Benzyloxy)phenyl)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-indol-5-amine(16C)

A mixture of Example 16B (4.5 g, 11.90 mmol),2-(tert-butyldimethylsilyloxy)ethanamine (4.17 g, 23.79 mmol) and cesiumcarbonate (11.63 g, 35.7 mmol) in toluene (30 mL) was degassed usingargon for 15 min and then palladium acetate (0.40 g, 1.78 mmol) andX-Phos (0.85 g, 1.78 mmol) were added. The resulting mixture was stirredat 100° C. for 12 h. The reaction mixture was warmed to roomtemperature, diluted into ethyl acetate and washed with water. Separatedorganic layer was dried over sodium sulfate and filtered. The filtratewas concentrated in vacuo and purified by flash chromatography using 10%ethyl acetate in hexane to afford the title compound (2.6 g, 46%) as asyrup. ¹H NMR (300 MHz, DMSO-d₆): δ 7.40-7.34 (m, 3H), 7.31 (d, J=3.3Hz, 1H), 7.28-7.20 (m, 5H), 7.10 (dt, J₁=1.5 Hz, J₂=7.5 Hz, 1H), 6.94(d, J=8.7 Hz, 1H), 6.71 (d, J=1.8 Hz, 1H), 6.56 (dd, J₁=8.7 Hz, J₂=2.1Hz, 1H), 6.39 (d, J=2.7 Hz, 1H), 5.11 (s, 2H), 4.93 (s, 1H), 3.76 (t,J=6.3 Hz, 2H), 3.16 (q, J=6.0 Hz, 2H), 0.88 (s, 9H), 0.02 (s, 6H).ESI-MS m/z=473 (M+H)⁺.

N-(1-(2-(Benzyloxy)phenyl)-1H-indol-5-yl)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,6-dichloropyrimidine-5-carboxamide(16D)

A solution of 4, 6-dichloropyrimidine-5-carbonyl chloride (1.39 g, 6.60mmol) in DCM (5 mL) was added dropwise to an ice-cold solution ofExample 16C (2.6 g, 5.50 mmol) and triethylamine (3.83 mL, 27.5 mmol) inDCM (30 mL), and the mixture was stirred for 1 h. This was thenconcentrated in vacuo, diluted into ethyl acetate and washed with water(2×20 mL). The separated organic layer was dried over sodium sulphateand filtered. The filtrate was concentrated in vacuo and purified byflash chromatography using 20% ethyl acetate in hexane to afford thetitle compound (2.8 g, 79%) as a yellow liquid. ¹H NMR (300 MHz,DMSO-d₆): δ 8.70 (s, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.52 (d, J=3.3 Hz,1H), 7.44 (m, 1H), 7.36 (dd, J₁=7.5 Hz, J₂=1.2 Hz, 2H), 7.24-7.21 (m,3H), 7.19-7.07 (m, 4H), 7.03 (d, J=9.0 Hz, 1H), 6.60 (d, J=3.3 Hz, 1H),5.08 (s, 2H), 3.98 (t, J=5.7 Hz, 2H), 3.78 (t, J=5.7 Hz, 2H), 0.85 (s,9H), 0.02 (s, 6H). ESI-MS m/z=647 (M+H)⁺.

N-(1-(2-(Benzyloxy)phenyl)-1H-indol-5-yl)-4,6-dichloro-N-(2-hydroxyethyl)pyrimidine-5-carboxamide(16E)

A solution of Example 16D (2.8 g, 4.32 mmol) in 15 mL of methanolicsolution of HCl (3N) was stirred at room temperature for 1 h. Methanolwas removed in vacuo, the residue was dissolved in ethyl acetate, andwashed with saturated aqueous sodium bicarbonate and saturated aqueousbrine. The separated organic layer was dried over sodium sulfate andfiltered, and the filtrate was concentrated in vacuo to afford the titlecompound (2.1 g, 91%) as an off-white solid, which was carried on to thenext step without further purification. ¹H NMR (300 MHz, DMSO-d₆): δ8.70 (s, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.52 (d, J=3.3 Hz, 1H), 7.42 (dd,J₁=7.5 Hz, J₂=1.5 Hz, 1H), 7.38 (s, 1H) 7.36 (d, J=1.5 Hz, 1H),7.28-7.22 (m, 3H), 7.19-7.03 (m, 5H), 6.63 (d, J=3.3 Hz, 1H), 5.09 (s,2H), 4.84 (s, 1H), 3.93 (t, J=6.0 Hz, 2H), 3.61 (q, J=4.8 Hz, 2H).ESI-MS m/z=533 (M+H)⁺.

6-(1-(2-(Benzyloxy)phenyl)-1H-indol-5-yl)-4-chloro-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(16F)

A solution of Example 16E (2.1 g, 3.94 mmol) and triethylamine (4.39 mL,31.5 mmol) in acetonitrile (20 mL) was stirred at 80° C. for 8 h. Thereaction mixture was cooled and concentrated in vacuo, and the residuewas partitioned between ethyl acetate and water. Separated organic layerwas dried over sodium sulfate and filtered, and the filtrate wasconcentrated in vacuo to afford the title compound (1.7 g, 87%) as anoff-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.83 (s, 1H), 7.67 (d,J=1.8 Hz, 1H), 7.58 (d, J=3.0 Hz, 1H), 7.46 (d, J=7.2 Hz, 2H), 7.39 (m,1H), 7.31-7.13 (m, 8H), 6.70 (d, J=3.3 Hz, 1H), 5.15 (s, 2H), 4.76 (t,J=5.4 Hz, 2H), 4.16 (t, J=4.8 Hz, 2H). ESI-MS m/z=497 (M+H)⁺.

4-Amino-6-(1-(2-(benzyloxy)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(16G)

A solution of Example 16F (1.7 g, 3.19 mmol) in 0.5 M ammonia in1,4-dioxane (20 mL) was stirred at room temperature for 2 h. Thereaction mixture was concentrated in vacuo, and the residue waspartitioned between ethyl acetate and water. Separated organic layer wasdried over sodium sulfate and filtered, and the filtrate wasconcentrated in vacuo to afford the title compound (1.3 g, 85%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.15 (s, 1H), 7.59 (bs,2H), 7.56 (d, J=1.6 Hz, 1H), 7.52 (d, J=3.2 Hz, 1H), 7.42 (d, J=7.6 Hz,2H), 7.35 (d, J=8.4 Hz, 1H), 7.26-7.18 (m, 5H), 7.15-7.05 (m, 3H), 6.63(d, J=2.8 Hz, 1H), 5.11 (s, 2H), 4.61 (t, J=4.4 Hz, 2H), 3.96 (t, J=4.4Hz, 2H). ESI-MS m/z=478 (M+H)⁺.

4-Amino-6-(1-(2-hydroxyphenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(16)

Ammonium formate (0.858 g, 13.6 mmol) and Pd/C (0.2 g, 1.879 mmol) wereadded to a solution of Example 16G (1.3 g, 2.72 mmol) in methanol (20mL) and stirred at 80° C. for 3 h. The reaction mixture was allowed towarm to room temperature, filtered through a pad of celite, and thefiltrate was concentrated in vacuo. The residue was diluted into ethylacetate, washed with water, dried over sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to afford the title compound (0.9 g,85% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.98 (s,1H), 8.18 (s, 1H), 7.62 (bs, 2H), 7.58 (d, J=1.2 Hz, 1H), 7.49 (d, J=3.0Hz, 1H), 7.30 (t, J=7.5 Hz, 2H), 7.15-7.06 (m, 3H), 6.97 (t, J=7.2 Hz,1H), 6.64 (d, J=3.3 Hz, 1H), 4.64 (t, J=4.5 Hz, 2H), 4.00 (t, J=4.5 Hz,2H). ESI-MS m/z=388 (M+H)⁺.

4-Amino-6-(1-(2-(cyclopentyloxy)phenyl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(17)

Cesium carbonate (0.5 g, 1.549 mmol) was added to a solution of Example16 (0.2 g, 0.516 mmol) and bromocyclopentane (0.092 g, 0.620 mmol) inDMF (8 mL), and the mixture was stirred at room temperature for 12 h.The reaction mixture was diluted into ethyl acetate, washed with water,dried over sodium sulfate and filtered. The filtrate was concentrated invacuo to afford the title compound (0.18 g, 73%) as off-white solid. ¹HNMR (300 MHz, DMSO-d₆): δ 8.18 (s, 1H), 7.62 (bs, 2H), 7.58 (s, 1H),7.47 (d, J=2.7 Hz, 1H), 7.43-7.39 (m, 2H), 7.27 (d, J=8.1 Hz, 1H),7.16-7.10 (m, 3H), 6.65 (d, J=3.0 Hz, 1H), 4.84 (m, 1H), 4.64 (t, J=5.1Hz, 2H), 4.0 (t, J=4.8 Hz, 2H), 1.78 (m, 2H), 1.57 (m, 2H), 1.50-1.40(m, 4H). ESI-MS m/z=456 (M+H)⁺; HPLC purity: 95.8%.

Examples 18-20 were prepared using procedures analogous to thosedescribed in Examples 16-17 with appropriate starting materials.

Exp Structure Analytical Data Mass/Purity 18

¹H NMR (300 MHz, DMSO-d₆): δ 9.90 (s, 1H), 8.19 (d, J = 1.8 Hz, 2H),8.05 (d, J = 2.1 Hz, 1H), 7.70-7.60 (m, 3H), 7.40 (dd, J₁ = 1.5 Hz, J₂ =8.1 Hz, 1H), 7.23 (m, 1H), 7.07 (dd, J₁ = 1.2 Hz, J₂ = 8.1 Hz, 1H), 6.95(dt, J₁ = 1.2 Hz, J₂ = 7.2 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H), 4.68 (t, J= 4.8 Hz, 2H), 4.05 (t, J = 4.5 Hz, 2H). ESI-MS m/z = 389 (M + H)⁺; LCMSpurity: 92.3%. 19

¹H NMR (400 MHz, DMSO-d₆): δ 8.18 (s, 2H), 8.04 (s, 1H), 7.64 (m, 3H),7.50 (d, J = 6.8 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 7.6 Hz,1H), 7.09 (t, J = 7.2 Hz, 1H), 6.66 (s, 1H), 4.84 (m, 1H), 4.67 (m, 2H),4.03 (m, 2H), 1.76 (m, 2H), 1.59 (m, 2H), 1.43 (m, 4H). ESI-MS m/z = 457(M + H)⁺; HPLC purity: 93%. 20

¹H NMR (400 MHz, DMSO-d₆): δ 8.18 (s, 1H), 7.62 (bs, 2H), 7.59 (d, J =2.0 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.46-7.38 (m, 2H), 7.29 (d, J =7.6 Hz, 1H), 7.15- 7.07 (m, 3H), 6.66 (d, J = 2.8 Hz, 1H), 4.64 (t, J =4.8 Hz, 2H), 4.08 (q, J = 6.8 Hz, 2H), 4.0 (t, J = 4.4 Hz, 2H), 1.17 (t,J = 7.2 Hz, 3H). ESI-MS m/z = 416 (M + H)⁺; HPLC purity: 94.3%.

Example 21

Procedures4-Amino-6-(1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-oneN′-Acetyl-5-bromo-1H-indole-1-carbohydrazide (21A)

Triethyl amine (8.89 mL, 63.8 mmol) and phosgene (20% in toluene) (18.92g, 38.3 mmol) were added to an ice-cold solution of 5-bromo-1H-indole (5g, 25.5 mmol) in THF (50 mL), and the mixture was stirred for 20 min.Acetohydrazide (2.267 g, 30.6 mmol) in THF (10 mL) was then added, andstirring was continued for 1 h at room temperature. The reaction mixturewas then diluted with water and extracted with ethyl acetate. Separatedorganic layer was dried over sodium sulphate and filtered, and thefiltrate was concentrated in vacuo to afford the title compound (3.8 g,49%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.15 (s, 1H),10.01 (s, 1H), 8.14 (d, J=9.2 Hz, 1H), 7.90 (d, J=4.0 Hz, 1H), 7.85 (d,J=2.0 Hz, 1H), 7.43 (dd, J₁=8.8 Hz, J₂=2.0 Hz, 1H), 6.74 (d, J=3.6 Hz,1H), 1.95 (s, 3H). ESI-MS m/z=296 (M−H)⁺.

2-(5-Bromo-1H-indol-1-yl)-5-methyl-1, 3, 4-oxadiazole (21B)

POCl₃ (0.944 mL, 10.13 mmol) was added to a solution of Example 21A (3.0g, 10.13 mmol) in toluene (30 mL), and the mixture was stirred at 110°C. for 2 h. The reaction mixture was then warmed to room temperature,poured into ice-cold water and extracted into ethyl acetate. Separatedorganic layer was dried over sodium sulphate and filtered, and thefiltrate was concentrated in vacuo to afford the title compound (2.1 g,73%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.13 (d, J=8.8Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.88 (d, J=4.0 Hz, 1H), 7.56 (dd,J₁=8.4 Hz, J₂=1.6 Hz, 1H), 6.89 (d, J=3.2 Hz, 1H), 2.59 (s, 3H). ESI-MSm/z=278 (M+H)⁺.

N-(2-(tert-Butyldimethylsilyloxy)ethyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indol-5-amine(21C)

A mixture of Example 21B (2.1 g, 7.55 mmol),2-(tert-butyldimethylsilyloxy) ethanamine (1.98 g, 11.33 mmol) andcesium carbonate (4.91 g, 15.1 mmol) in toluene (30 mL) was degassed for15 min under argon. Palladium acetate (0.339 g, 1.51 mmol) and X-Phos(0.719 g, 1.51 mmol) were then added and the reaction mixture wasstirred at 120° C. for 16 h. The reaction mixture was cooled andpartitioned between ethyl acetate and water. Separated organic layer wasdried over sodium sulphate and filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatographyusing 30% dichloromethane in hexanes to afford the title compound (1 g,29%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.87 (d, J=9.0Hz, 1H), 7.62 (d, J=3.6 Hz, 1H), 6.78-6.75 (m, 2H), 6.66 (d, J=3.3 Hz,1H), 5.39 (t, J=5.4 Hz, 1H), 3.75 (t, J=6.3 Hz, 2H), 3.18 (q, J=6.0 Hz,2H), 2.54 (s, 3H), 0.87 (s, 9H), 0.03 (s, 6H). ESI-MS m/z=373 (M+H)⁺.

N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indol-5-yl)pyrimidine-5-carboxamide(21D)

A solution of 4,6-dichloropyrimidine-5-carbonyl chloride (0.675 g, 3.21mmol) in DCM (10 mL) was added dropwise to an ice-cold solution ofExample 21C (1.0 g, 2.68 mmol) and triethylamine (0.374 mL, 4.02 mmol)in DCM (20 mL) and stirred for 1 h. The reaction mixture wasconcentrated in vacuo, diluted with ethyl acetate, washed with water(2×10 mL). Separated organic layer was dried over sodium sulphate andfiltered, and the filtrate was concentrated in vacuo. The residue waspurified by flash chromatography using 15% ethyl acetate in hexanes toafford the title compound (0.95 g, 53%) as a pale yellow solid. ¹H NMR(300 MHz, DMSO-d₆): δ 8.74 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.84 (d,J=3.9 Hz, 1H), 7.80 (s, 1H), 7.45 (d, J=8.7 Hz, 1H), 6.86 (d, J=3.6 Hz,1H), 4.03 (t, J=4.5 Hz, 2H), 3.80 (t, J=5.1 Hz, 2H), 2.55 (s, 3H), 0.85(s, 9H), 0.02 (s, 6H). ESI-MS m/z=547 (M+H)⁺.

4,6-Dichloro-N-(2-hydroxyethyl)-N-(1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indol-5-yl)pyrimidine-5-carboxamide(21E)

A solution of Example 21D (0.95 g, 1.735 mmol) in 20 mL of methanolicsolution of HCl (3% HCl in MeOH) was stirred at room temperature for 1h. Methanol was removed in vacuo, and the residue was dissolved in ethylacetate, washed with saturated aqueous sodium bicarbonate and saturatedaqueous brine. The separated organic layer was dried over sodium sulfateand filtered, and the filtrate was concentrated in vacuo to afford thetitle compound (0.5 g, 43%) as a pale yellow solid, which was carried onto the next step without further purification. ¹H NMR (300 MHz,DMSO-d₆): δ 8.73 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.84 (d, J=3.6 Hz,1H), 7.83 (d, J=1.8 Hz, 1H), 7.46 (dd, J₁=9.0 Hz, J₂=1.8 Hz, 1H), 6.90(d, J=3.3 Hz, 1H), 4.87 (bs, 1H), 3.96 (t, J=6.3 Hz, 2H), 3.63 (q, J=5.1Hz, 2H), 2.55 (s, 3H). ESI-MS m/z=433 (M+H)⁺.

4-Chloro-6-(1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(21F)

A solution of Example 21E (0.5 g, 1.154 mmol) and TEA (0.8 mL, 5.77mmol) in acetonitrile (20 mL) was stirred at 80° C. for 16 h. Thereaction mixture was cooled and concentrated in vacuo, and the residuewas partitioned between ethyl acetate and water. Separated organic layerwas dried over sodium sulfate and filtered, and the filtrate wasconcentrated in vacuo to afford the title compound (0.3 g, 65%) as apale yellow solid that was carried on to the next step without furtherpurification

4-Amino-6-(1-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(21)

A solution of Example 21F (0.3 g, 0.756 mmol) in 0.5 M ammonia in 1,4-dioxane (15 mL) was stirred at room temperature for 3 h. The reactionmixture was concentrated in vacuo, and the residue was partitionedbetween ethyl acetate and water. Separated organic layer was dried oversodium sulfate and filtered, and the filtrate was concentrated in vacuoto give a solid mass. This solid material was triturated with diethylether to afford the title compound (0.12 g, 40%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 8.21 (d, J=8.8 Hz, 1H), 8.18 (s, 1H), 7.89 (d,J=3.2 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.64 (bs, 2H), 7.41 (dd, J₁=8.8Hz, J₂=2.0 Hz, 1H), 6.93 (d, J=3.2 Hz, 1H), 4.66 (t, J=4.0 Hz, 2H), 4.04(t, J=4.8 Hz, 2H), 2.58 (s, 3H). ESI-MS m/z=378 (M+H)⁺; LCMS purity:95%; HPLC purity: 94%.

Example 22

Procedures4-Amino-6-(7-cyclopropyl-1-propyl-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one7-Bromo-5-nitroindoline (22A)

Bromine (1.569 mL, 30.5 mmol) was added dropwise to an ice-cold solutionof 5-nitro indoline (5 g, 30.5 mmol) in acetic acid (50 mL), and themixture was stirred for 1 h. Acetic acid was concentrated under reducedpressure, and the resulting solid was triturated with water to affordthe title compound (6 g, 80%) as a yellow solid, which was carried on tothe next step without further purification. ¹H NMR (300 MHz, DMSO-d₆): δ8.07 (d, J=2.1 Hz, 1H), 7.84 (d, J=2.1 Hz, 1H), 7.3 (bs, 1H), 3.7 (t,J=8.7 Hz, 2H), 3.17 (t, J=8.4 Hz, 2H). ESI-MS m/z=243 (M+H)⁺.

7-Bromo-5-nitro-1H-indole (22B)

DDQ (5.6 g, 24.69 mmol) and isopropanol (2 mL) were added to a solutionof Example 22A (3 g, 12.34 mmol) in ethanol (30 mL), and the mixture wasstirred at 80° C. for 48 h. The reaction mixture was concentrated underreduced pressure, and the residue was partitioned between ethyl acetateand water. Separated organic layer was washed with water, dried oversodium sulphate, filtered and the filtrate was concentrated in vacuo.The crude product was purified by flash chromatography using 20% ethylacetate in hexane to afford the title compound (2.5 g, 84%) as a yellowsolid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.13 (bs, 1H), 8.62 (d, J=1.8 Hz,1H), 8.18 (d, J=1.8 Hz, 1H), 7.67 (t, J=3.0 Hz, 1H), 6.89 (m, 1H).ESI-MS m/z=241 (M+H)⁺.

7-Bromo-5-nitro-1-propyl-1H-indole (22C)

1-Bromopropane (1.53 g, 12.45 mmol) and cesium carbonate (10.14 g, 31.1mmol) were added to a solution of Example 22B (2.5 g, 10.37 mmol) in DMF(5 mL), and the mixture was stirred at 70° C. for 1 h. DMF was removedunder reduced pressure, and the residue was partitioned between ethylacetate and water. Separated organic layer was washed with water, driedover sodium sulphate and filtered, and the filtrate was concentrated invacuo. The crude product was purified by flash chromatography using 10%ethyl acetate in hexane to afford the title compound (2 g, 64%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.56 (d, J=2.0 Hz, 1H), 8.12(d, J=2.4 Hz, 1H), 7.69 (d, J=3.2 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 4.5(t, J=7.6 Hz, 2H), 1.77 (m, 2H), 0.83 (t, J=7.6 Hz, 3H). ESI-MS m/z=283(M+H)⁺.

7-Cyclopropyl-5-nitro-1-propyl-1H-indole (22D)

PdCl₂(dppf)-CH₂Cl₂ adduct (0.517 g, 0.706 mmol) was added to a solutionof 22C (2 g, 7.06 mmol) in 15 mL of toluene kept under argon, followedby addition of cesium carbonate (6.90 g, 21.19 mmol) and cyclopropylboronic acid (0.728 g, 8.48 mmol). The mixture was then degassed for 5min and stirred at 100° C. for 2 h. The reaction mixture was warmed toroom temperature and partitioned between ethyl acetate and water.Separated organic layer was washed with water, dried over sodiumsulphate and filtered, and the filtrate was concentrated in vacuo. Thecrude product was purified by flash chromatography using 10% ethylacetate in hexane to afford the title compound (1.8 g, 69%) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (d, J=2.4 Hz, 1H), 7.68 (d,J=1.2 Hz, 1H), 7.62 (d, J=3.6 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 4.6 (t,J=7.2 Hz, 2H), 2.45 (m, 1H), 1.85-1.76 (m, 2H), 1.16-1.02 (m, 2H),0.93-0.85 (m, 5H). ESI-MS m/z=245.2 (M+H)⁺.

7-Cyclopropyl-1-propyl-1H-indol-5-amine (22E)

Palladium on carbon (0.157 g, 1.474 mmol) was added to a solution ofExample 22D (1.8 g, 7.37 mmol) in ethanol (20 mL), and the mixture wasstirred under hydrogen atmosphere for 16 h at room temperature. Thereaction mixture was then filtered through a pad of celite, and thefiltrate was concentrated under reduced pressure. The crude residue waspurified by flash chromatography using 25% ethyl acetate in hexane toafford the title compound (1 g, 57%) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆): δ 7.08 (d, J=2.4 Hz, 1H), 6.49 (d, J=1.6 Hz, 1H), 6.26(d, J=1.6 Hz, 1H), 6.08 (d, J=2.8 Hz, 1H), 4.42-4.28 (m, 4H), 2.22 (m,1H), 1.76-1.62 (m, 2H), 0.94-0.88 (m, 2H), 0.84 (t, J=7.2 Hz, 3H), 0.70(q, J=5.6 Hz, 2H). ESI-MS m/z=215 (M+H)⁺.

N-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-7-cyclopropyl-1-propyl-1H-indol-5-amine(22F)

(2-Bromoethoxy) (tert-butyl) dimethylsilane (1.116 g, 4.67 mmol) andpotassium carbonate (2.58 g, 18.66 mmol) were added to a solution ofExample 22E (1 g, 4.67 mmol) in acetonitrile (10 mL), and the mixturewas stirred at 80° C. for 24 h. Acetonitrile was removed under vacuum,and the residue was partitioned between ethyl acetate and water.Separated organic layer was dried over sodium sulphate and filtered, andthe filtrate was concentrated in vacuo. The crude product was purifiedby flash column chromatography using 5% ethyl acetate in hexane toafford the title compound (0.6 g, 34%) as a colorless syrup. ¹H NMR (300MHz, DMSO-d₆): δ 7.10 (d, J=3.0 Hz, 1H), 6.46 (d, J=1.8 Hz, 1H), 6.29(d, J=1.8 Hz, 1H), 6.14 (d, J=3.0 Hz, 1H), 4.73 (t, J=5.7 Hz, 1H), 4.38(t, J=7.2 Hz, 2H), 3.71 (t, J=6.3 Hz, 2H), 3.09 (q, J=6.3 Hz, 2H),2.26-2.22 (m, 1H), 1.76-1.68 (m, 2H), 0.98-0.82 (m, 14H), 0.75-0.68 (m,2H), 0.04 (s, 6H). ESI-MS m/z=373 (M+H)⁺.

N-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-4,6-dichloro-N-(7-cyclopropyl-1-propyl-1H-indol-5-yl)pyrimidine-5-carboxamide (22G)

A solution of 4,6-dichloropyrimidine-5-carbonyl chloride (0.849 g, 4.5mmol) in DCM (10 mL) was added dropwise to an ice-cold solution ofExample 22F (0.47 g, 2.415 mmol) and triethylamine (1.87 mL, 13.4 mmol)in DCM (30 mL), and the mixture was stirred for 1 h. The reaction wasdiluted with dichloromethane and washed with water. Separated organiclayer was dried over sodium sulphate and filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatographyusing 20% ethyl acetate in hexanes to afford the title compound (0.5 g,57%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.7 (s, 1H),7.48 (d, J=1.8 Hz, 1H), 7.35 (d, J=3.3 Hz, 1H), 6.8 (d, J=1.8 Hz, 1H),6.38 (d, J=3.3 Hz, 1H), 4.42 (t, J=7.5 Hz, 2H), 3.96 (t, J=2.1 Hz, 2H),3.76 (t, J=5.4 Hz, 2H), 2.31-2.22 (m, 1H), 1.71 (q, J=7.8 Hz, 2H),0.98-0.72 (m, 2H), 0.88-0.78 (m, 12H), 0.62-0.56 (m, 2H), 0.023 (s, 6H).ESI-MS m/z=547 (M+H)⁺.

4,6-Dichloro-N-(7-cyclopropyl-1-propyl-1H-indol-5-yl)-N-(2-hydroxyethyl)pyrimidine-5-carboxamide(22H)

A solution of Example 22G (0.5 g, 0.913 mmol) in 20 mL of methanolicsolution of HCl (3% HCl in MeOH) was stirred at room temperature for 1h. Methanol was removed in vacuo, the residue dissolved in ethylacetate, and washed with saturated aqueous sodium bicarbonate andsaturated aqueous brine. The separated organic layer was dried oversodium sulfate and filtered, and the filtrate was concentrated in vacuoto afford the title compound (0.3 g, 61%) as an off-white solid, whichwas carried on to the next step without further purification. ¹H NMR(300 MHz, DMSO-d₆): δ 8.7 (s, 1H), 7.47 (d, J=1.8 Hz, 1H), 7.35 (d,J=3.3 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 6.41 (d, J=2.7 Hz, 1H), 4.82 (t,J=5.4 Hz, 1H), 4.43 (t, J=7.2 Hz, 2H), 3.89 (t, J=6.6 Hz, 2H), 3.60 (q,J=6.0 Hz, 2H), 2.38-2.22 (m, 1H), 1.76-1.68 (m, 2H), 1.02-0.92 (m, 2H),0.84 (t, J=7.5 Hz, 3H), 0.65-0.58 (m, 2H). ESI-MS m/z=433 (M+H)⁺.

4-Chloro-6-(7-cyclopropyl-1-propyl-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(221)

A solution of Example 22H (0.3 g, 0.692 mmol) and triethylamine (0.8 mL,5.77 mmol) in acetonitrile (20 mL) was stirred at 80° C. for 16 h. Thereaction mixture was cooled and concentrated in vacuo, and the residuewas partitioned between ethyl acetate and water. Separated organic layerwas dried over sodium sulfate and filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatographyusing 20% ethyl acetate in hexane to afford the title compound (0.22 g,72%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.81 (s, 1H),7.41 (m, 2H), 6.83 (s, 1H), 6.48 (d, J=3.0 Hz, 1H), 4.72 (t, J=4.5 Hz,2H), 4.55 (t, J=7.5 Hz, 2H), 4.11 (t, J=4.8 Hz, 2H), 2.42-2.30 (m, 1H),1.88-1.72 (m, 2H), 1.04-0.85 (m, 2H), 0.89 (t, J=7.2 Hz, 3H), 0.82 (m,2H). ESI-MS m/z=397.1 (M+H)⁺.

4-Amino-6-(7-cyclopropyl-1-propyl-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (22)

A solution of Example 221 (0.25 g, 0.630 mmol) in 0.5 M ammonia in 1,4-dioxane (15 mL) was stirred at room temperature for 3 h. The reactionmixture was concentrated in vacuo, and the residue was partitionedbetween ethyl acetate and water. Separated organic layer was dried oversodium sulfate and filtered, and the filtrate was concentrated in vacuoto give a solid mass, which was triturated with diethyl ether to affordthe title compound (0.19 g, 76%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.16 (s, 1H), 7.60 (bs, 2H), 7.38 (d, J=3.2 Hz, 1H), 7.33(d, J=2.0 Hz, 1H), 6.79 (d, J=1.2 Hz, 1H), 6.44 (d, J=3.2 Hz, 1H), 4.61(t, J=4.4 Hz, 2H), 4.53 (t, J=7.2 Hz, 2H), 3.95 (t, J=4.4 Hz, 2H),2.40-2.32 (m, 1H), 1.80-1.76 (m, 2H), 0.99 (m, 2H), 0.88 (t, J=7.6 Hz,3H), 0.84-0.80 (m, 2H). ESI-MS m/z=378.1 (M+H)⁺; LCMS purity: 94%.

Example 23

ProceduresN-(5-(4-Amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-1-(2-methoxyphenyl)-1H-indol-7-yl)cyclopropanecarboxamideN-(5-Bromo-1H-indol-7-yl)cyclopropanecarboxamide (23A)

A solution of cyclopropanecarbonyl chloride (0.54 g, 5.21 mmol) in DCM(10 mL) was added dropwise to an ice-cold solution of5-bromo-1H-indol-7-amine (1.0 g, 4.74 mmol) and triethylamine (0.991 mL,7.11 mmol) in DCM (20 mL), and the mixture was stirred for 2 h. Thereaction mixture was concentrated in vacuo and partitioned between ethylacetate and water. Separated organic layer was dried over sodiumsulphate and filtered, and the filtrate was concentrated in vacuo. Theresidue was purified by flash chromatography using 20% ethyl acetate inhexanes to afford the title compound (1.1 g, 76%) as a red solid. ¹H NMR(300 MHz, DMSO-d₆): δ 11.0 (s, 1H), 10.08 (s, 1H), 7.72 (s, 1H), 7.48(s, 1H), 7.41 (t, J=3.0 Hz, 1H), 6.43 (t, J=2.4 Hz, 1H), 1.90-1.86 (m,1H), 0.88-0.82 (m, 4H). ESI-MS m/z=279 (M+H)⁺.

N-(5-Bromo-1-(2-methoxyphenyl)-1H-indol-7-yl)cyclopropanecarboxamide(23B)

1-Iodo-2-methoxybenzene (1.06 g, 4.30 mmol) was added to a solution ofExample 23A (1.0 g, 3.58 mmol) and copper(I) bromide (0.051 g, 0.358mmol) in toluene (20 mL), followed by addition of potassium carbonate(0.99 g, 7.17 mmol), and the mixture was stirred at 100° C. for 10 min.NaOH (100 mg, 2.69 mmol) and copper(II) acetate (65.0 mg, 0.358 mmol)were then added at 100° C., and the reaction mixture was stirred for 6h. Insoluble solids were filtered, the filtrate was concentrated, andthe residue was partitioned between ethyl acetate and water. Separatedorganic layer was dried over sodium sulphate and filtered. The filtratewas concentrated in vacuo and purified by flash chromatography using 10%ethyl acetate in hexanes to afford the title compound (0.4 g, 29%) as ared solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.14 (s, 1H), 7.69 (d, J=1.6 Hz,1H), 7.41 (dt, J₁=1.6 Hz, J₂=8.8 Hz, 1H), 7.28 (d, J=3.2 Hz, 1H), 7.19(d, J=6.4 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.01-6.97 (m, 2H), 6.60 (d,J=2.8 Hz, 1H), 3.64 (s, 3H), 1.08 (m, 1H), 0.47-0.32 (m, 4H). ESI-MSm/z=385 (M+H)⁺.

N-(5-(2-(tert-Butyldimethylsilyloxy)ethylamino)-1-(2-methoxyphenyl)-1H-indol-7-yl)cyclopropanecarboxamide(23C)

A mixture of Example 23B (0.4 g, 1.038 mmol),2-(tert-butyldimethylsilyloxy)ethanamine (0.21 g, 1.246 mmol), cesiumcarbonate (0.677 g, 2.077 mmol), palladium acetate (0.0233 g, 0.104mmol) and X-Phos (0.0495 g, 0.104 mmol) in toluene (15 mL) under argonwas stirred at 100° C. for 7 h. The reaction was warmed to roomtemperature, diluted into ethyl acetate and washed with water. Separatedorganic layer was dried over sodium sulfate and filtered, and thefiltrate was concentrated under vacuum to obtain dark oil. The residuewas purified by flash chromatography using 15% ethyl acetate in hexanesto afford the title compound (0.15 g, 22%) as a syrup. ¹H NMR (300 MHz,DMSO-d₆): δ 8.85 (s, 1H), 7.33 (t, J=10 Hz, 1H), 7.13-6.92 (m, 4H), 6.60(s, 1H), 6.37 (d, J=2.0 Hz, 1H), 6.35 (d, J=4.0 Hz, 1H), 4.97 (t, J=5.7Hz, 1H), 3.75 (t, J=6.0 Hz, 2H), 3.65 (s, 3H), 3.16 (q, J=6.3 Hz, 2H),1.09 (m, 1H), 0.88 (s, 9H), 0.39-0.35 (m, 4H), 0.06 (s, 6H). ESI-MSm/z=480 (M+H)⁺.

N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(7-(cyclopropanecarboxamido)-1-(2-methoxyphenyl)-1H-indol-5-yl)pyrimidine-5-carboxamide(23D)

A solution of 4,6-dichloropyrimidine-5-carbonyl chloride (0.079 g, 0.375mmol) in DCM (2 mL) was added dropwise to an ice-cold solution ofExample 23C (0.15 g, 0.313 mmol) and triethylamine (0.29 mL, 2.06 mmol)in DCM (20 mL), and the mixture was stirred for 2 h. The reactionmixture was concentrated in vacuo, and the residue was partitionedbetween ethyl acetate and water. Separated organic layer was dried oversodium sulphate and filtered, and the filtrate was concentrated invacuo. The residue was purified by flash chromatography using 20% ethylacetate in hexane to afford the title compound (0.19 g, 85%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.00 (s, 1H), 8.77 (s, 1H), 7.58 (s,1H), 7.38 (dt, J₁=1.2 Hz, J₂=8.8 Hz, 1H), 7.25 (d, J=3.2 Hz, 1H), 7.12(d, J=7.2 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.99-6.94 (m, 2H), 6.56 (d,J=2.8 Hz, 1H), 3.97 (m, 2H), 3.82 (t, J=5.6 Hz, 2H), 3.58 (s, 3H), 1.07(m, 1H), 0.87 (s, 9H), 0.42-0.36 (m, 4H), 0.049 (s, 6H).

4,6-Dichloro-N-(7-(cyclopropanecarboxamido)-1-(2-methoxyphenyl)-1H-indol-5-yl)-N-(2-hydroxyethyl)pyrimidine-5-carboxamide(23E)

TBAF (0.152 g, 0.58 mmol) in THF (10 mL) was added to a solution ofExample 23D (0.3 g, 0.575 mmol) in THF (5 mL), and the mixture wasstirred at room temperature for 2 h. THF was removed in vacuo and theresidue was partitioned between ethyl acetate and water. The separatedorganic layer was dried over sodium sulfate and filtered, and thefiltrate was concentrated in vacuo to afford the title compound (0.13 g,78%) as a yellow syrup, which was carried on to the next step withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆): δ 9.02 (s, 1H), 8.76(s, 1H), 7.59 (s, 1H), 7.36 (dt, J₁=1.6 Hz, J₂=8.8 Hz, 1H), 7.26 (d,J=3.2 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 7.00-6.94(m, 2H), 6.59 (d, J=2.8 Hz, 1H), 4.87 (bs, 1H), 3.92 (t, J=6.8 Hz, 2H),3.64 (t, J=4.8 Hz, 2H), 3.59 (s, 3H), 1.08 (m, 1H), 0.43-0.36 (m, 4H).ESI-MS m/z=540 (M+H)⁺.

N-(5-(4-Chloro-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-1-(2-methoxyphenyl)-1H-indol-7-yl)cyclopropanecarboxamide(23F)

A slurry of Example 23E (0.13 g, 0.241 mmol) and triethylamine (0.067mL, 0.481 mmol) in acetonitrile (20 mL) was stirred at 80° C. for 3 h.The reaction mixture was cooled and concentrated in vacuo, and theresidue was partitioned between ethyl acetate and water. Separatedorganic layer was dried over sodium sulfate and filtered, and thefiltrate was concentrated in vacuo to afford the title compound (0.09 g,68.3%) as a thick syrup. ¹H NMR (300 MHz, DMSO-d₆): δ 9.21 (s, 1H), 8.80(s, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.41 (dt, J₁=1.5 Hz, J₂=9.3 Hz, 1H),7.31 (d, J=3.0 Hz, 1H), 7.19 (d, J=6.6 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H),7.00 (t, J=7.2 Hz, 1H), 6.93 (d, J=1.5 Hz, 1H), 6.67 (d, J=3.3 Hz, 1H),4.78 (t, J=4.2 Hz, 2H), 4.16 (t, J=4.5 Hz, 2H), 3.68 (s, 3H), 1.14 (m,1H), 0.46-0.32 (m, 4H). ESI-MS m/z=504 (M+H)⁺.

N-(5-(4-Amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-1-(2-methoxyphenyl)-1H-indol-7-yl)cyclopropanecarboxamide(23)

A solution of product of Example 23F (0.090 g, 0.179 mmol), in 0.5 Mammonia in 1,4-dioxane (2 mL) was stirred at room temperature for 2 h.The reaction mixture was concentrated in vacuo, and the residue waspartitioned between ethyl acetate and water. Separated organic layer wasdried over sodium sulfate and filtered, and the filtrate wasconcentrated in vacuo to give a solid mass, which was triturated withdiethyl ether to afford the title compound (0.07 g, 65%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.18 (s, 1H), 7.63(bs, 2H), 7.50 (s, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.28 (d, J=2.8 Hz, 1H),7.19 (d, J=7.6 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.00 (t, J=7.2 Hz, 1H),6.89 (d, J=1.2 Hz, 1H), 6.63 (d, J=3.2 Hz, 1H), 4.65 (t, J=4.4 Hz, 2H),4.00 (t, J=3.6 Hz, 2H), 3.68 (s, 3H), 1.10 (m, 1H), 0.45-0.31 (m, 4H).ESI-MS m/z=485 (M+H)⁺; HPLC purity: 95%.

Examples 24-25 were prepared using procedures analogous to thosedescribed in Examples 21-23 using appropriate starting materials.

Exp Structure Analytical Data Mass/Purity 24

¹H NMR (400 MHz, DMSO-d₆): δ 8.13 (s, 1H), 7.58 (bs, 2H), 7.52 (d, J =3.6 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 6.47(d, J = 3.2 Hz, 1H), 5.72 (m, 1H), 4.59 (t, J = 4.4 Hz, 2H), 3.94 (t, J= 4.4 Hz, 2H), 3.86 (d, J = 10.8 Hz, 2H), 3.66 (dt, J₁ = 2.4 Hz, J₂ =10.8 Hz, 2H), 2.96-2.82 (m, 4H), 1.38 (d, J = 6.4 Hz, 6H). ESI-MS m/z =423 (M + H)⁺; HPLC purity: 92%. 25

¹H NMR (300 MHz, DMSO-d₆): δ 10.05 (s, 1H), 8.17 (s, 1H), 7.62 (bs, 2H),7.55 (d, J = 3.3 Hz, 1H), 7.43 (d, J = 1.2 Hz, 1H), 6.84 (s, 1H), 6.53(d, J = 3.3 Hz, 1H), 5.03 (m, 1H), 4.63 (t, J = 4.5 Hz, 2H), 3.97 (m,2H), 1.85 (m, 1H), 1.39 (d, J = 6.6 Hz, 6H), 0.90-0.72 (m, 4H). ESI-MSm/z = 421 (M + H)⁺; HPLC purity: 99.48%.

Example 26

Procedures4-Amino-6-(7-cyclopropyl-1-(6-methylpyridin-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one7-Cyclopropyl-5-nitro-1H-indole (26A)

PdCl₂ (dppf)-CH₂Cl₂ adduct (7.59 g, 10.37 mmol) was added to a solutionof 22B (25 g, 104 mmol) in 500 mL of toluene and water (1:1) kept underargon atmosphere. Cesium carbonate (40.6 g, 124 mmol) and cyclopropylboronic acid (17.82 g, 207 mmol) were then added. The mixture wasdegassed for 5 min and stirred at 100° C. for 16 h. The reaction mixturewas allowed to room temperature and partitioned between ethyl acetateand water. Separated organic layer was washed with water, dried oversodium sulphate, and filtered. The filtrate was concentrated in vacuo.The crude product was purified by flash chromatography using 20% ethylacetate in hexane to afford title compound (17 g, 79%) as a yellowsolid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.98 (s, 1H), 8.40 (d, J=1.8 Hz,1H), 7.62 (t, J=3.0 Hz, 1H), 7.49 (d, J=2.1 Hz, 1H), 6.75 (dd, J₁=1.8Hz, J₂=3.0 Hz, 1H), 2.35 (m, 1H), 1.13-1.05 (m, 2H), 0.87-0.80 (m, 2H).ESI-MS m/z=201 (M−H)⁻.

7-Cyclopropyl-1H-indol-5-amine (26B)

Palladium on carbon (3 g, 28.2 mmol) was added to a solution of 26A (15g, 74.2 mmol) in ethanol (200 mL), and the mixture was stirred underhydrogen atmosphere for 16 h at room temperature. The reaction mixturewas filtered through a pad of celite, and the filtrate was concentratedunder reduced pressure. The crude product was purified by flashchromatography using 30% ethyl acetate in hexane to afford titlecompound (12 g, 93%) as a pale yellow viscous liquid. ¹H NMR (300 MHz,DMSO-d₆): δ 10.62 (s, 1H), 7.11 (t, J=2.7 Hz, 1H), 6.48 (d, J=2.1 Hz,1H), 6.12 (dd, J₁=2.1 Hz, J₂=3.0 Hz, 1H), 6.04 (d, J=1.8 Hz, 1H), 4.30(s, 2H), 2.14 (m, 1H), 0.96-0.90 (m, 2H), 0.65-0.60 (m, 2H). ESI-MSm/z=173 (M+H)⁺.

tert-Butyl 7-cyclopropyl-1H-indol-5-ylcarbamate (26C)

Triethylamine (14.57 g, 105 mmol) was added to a solution of 26B (12 g,69.7 mmol) in methanol (150 mL) followed by di-tert-butyl dicarbonate(17.79 g, 77 mmol), and the mixture was stirred for 2 h at 0° C. MeOHwas removed in vacuo, and the residue was partitioned between ethylacetate and water. The separated organic layer was dried over sodiumsulfate and filtered, and the filtrate was concentrated in vacuo toafford title compound (18 g, 95%) as an off white solid. ¹H NMR (300MHz, DMSO-d₆): δ 10.99 (s, 1H), 8.86 (s, 1H), 7.44 (s, 1H), 7.26 (t,J=2.7 Hz, 1H), 6.71 (d, J=1.2 Hz, 1H), 6.32 (dd, J₁=1.8 Hz, J₂=3.0 Hz,1H), 2.20 (m, 1H), 1.46 (s, 9H), 1.01-0.94 (m, 2H), 0.66-0.61 (m, 2H).ESI-MS m/z=273 (M+H)⁺.

tert-Butyl 7-cyclopropyl-1-(6-methylpyridin-3-yl)-1H-indol-5-ylcarbamate(26D)

Copper (I) iodide (0.28 g, 1.46 mmol) and(R,R)—N,N′-dimethyl-1,2-cyclohexanediamine (0.208 g, 1.46 mmol) wereadded to a solution of 26C (2 g, 7.35 mmol) in 1,4-dioxane (20 mL) underargon atmosphere, followed by 5-bromo-2-methylpyridine (1.9 g, 11.02mmol) and potassium phosphate (3.12 g, 14.7 mmol). The mixture was thendegassed for 5 min and stirred at 110° C. for 16 h. Insoluble solidswere filtered, the filtrate was concentrated, and the residue waspartitioned between ethyl acetate and water. Separated organic layer wasdried over sodium sulphate and filtered, and the filtrate wasconcentrated in vacuo. The crude product was purified by flashchromatography using 15% ethyl acetate in hexane to afford titlecompound (0.26 g, 9.7%) as an off white solid. ¹H NMR (300 MHz,DMSO-d₆): δ 9.04 (s, 1H), 8.55 (d, J=2.1 Hz, 1H), 7.80 (dd, J₁=2.4 Hz,J₂=8.1 Hz, 1H), 7.63 (bs, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.31 (d, J=3.3Hz, 1H), 6.95 (s, 1H), 6.57 (d, J=2.7 Hz, 1H), 2.55 (s, 3H), 1.47 (s,9H), 1.46 (m, 1H), 0.45-0.30 (m, 4H). ESI-MS m/z=363 (M+H)⁺.

7-Cyclopropyl-1-(6-methylpyridin-3-yl)-1H-indol-5-amine (26E)

A solution of 26D (1.6 g, 4.4 mmol) and 4 N HCl in 1,4-dioxane solution(20 mL) was stirred at room temperature for 2 h. 1,4-Dioxane was thenremoved in vacuo, the residue dissolved in ethyl acetate andsequentially washed with saturated aqueous sodium bicarbonate and brine.The separated organic layer was dried over sodium sulfate and filtered,and the filtrate was concentrated in vacuo to afford title compound (1g, 83%) as a colorless liquid, which was carried on to the next stepwithout further purification. ¹H NMR (300 MHz, DMSO-d₆): δ 8.51 (d,J=2.1 Hz, 1H), 7.75 (dd, J₁=2.7 Hz, J₂=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz,1H), 7.15 (d, J=3.3 Hz, 1H), 6.60 (d, J=1.8 Hz, 1H), 6.37 (d, J=3.3 Hz,1H), 6.28 (d, J=1.2 Hz, 1H), 4.54 (bs, 2H), 2.53 (s, 3H), 1.40 (m, 1H),0.46-0.28 (m, 4H). ESI-MS m/z=264 (M+H)⁺.

N-(2-(tert-Butyldimethylsilyloxy)ethyl)-7-cyclopropyl-1-(6-methylpyridin-3-yl)-1H-indol-5-amine(26F)

(2-Bromoethoxy) (tert-butyl) dimethylsilane (0.908 g, 3.8 mmol) andpotassium carbonate (1.57 g, 11.39 mmol) were added to a solution of 26E(1 g, 3.8 mmol) in acetonitrile (20 mL), and the mixture was stirred at80° C. for 16 h. Acetonitrile was removed in vacuo, and the residue waspartitioned between ethyl acetate and water. Separated organic layer wasdried over sodium sulphate and filtered, and the filtrate wasconcentrated in vacuo. The crude product was purified by flash columnchromatography using 10% ethyl acetate in hexane to afford titlecompound (1.2 g, 73.3%) as an off white solid. ¹H NMR (300 MHz,DMSO-d₆): δ 8.52 (d, J=2.4 Hz, 1H), 7.77 (dd, J₁=2.7 Hz, J₂=7.8 Hz, 1H),7.36 (d, J=8.1 Hz, 1H), 7.17 (d, J=3.3 Hz, 1H), 6.57 (d, J=2.1 Hz, 1H),6.42 (d, J=3.3 Hz, 1H), 6.32 (s, 1H), 4.95 (t, J=6.3 Hz, 1H), 3.75 (t,J=6.0 Hz, 2H), 3.16 (q, J=6.3 Hz, 2H), 2.53 (s, 3H), 1.42 (m, 1H), 0.86(s, 9H), 0.45-0.28 (m, 4H), 0.02 (s, 6H). ESI-MS m/z=422 (M+H)⁺.

N-(2-(tert-Butyldimethylsilyloxy)ethyl)-4,6-dichloro-N-(7-cyclopropyl-1-(6-methylpyridin-3-yl)-1H-indol-5-yl)pyrimidine-5-carboxamide(26G)

A solution of 4,6-dichloropyrimidine-5-carbonyl chloride (0.824 g, 4.27mmol) in DCM (20 mL) was added drop-wise to an ice-cold solution of 26F(1.2 g, 2.85 mmol) and triethylamine (1.19 ml, 8.54 mmol) in DCM (25mL), and the mixture was stirred for 1 h. The reaction was diluted withdichloromethane and washed with water. The separated organic layer wasdried over sodium sulphate and filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatographyusing 20% ethyl acetate in hexane to afford title compound (1.3 g, 77%)as an off white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.74 (s, 1H), 8.51(d, J=2.7 Hz, 1H), 7.79 (dd, J₁=2.7 Hz, J₂=8.7 Hz, 1H), 7.62 (d, J=1.8Hz, 1H), 7.42 (d, J=3.3 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 6.85 (d, J=1.2Hz, 1H), 6.64 (d, J=3.3 Hz, 1H), 3.99 (t, J=5.4 Hz, 2H), 3.78 (t, J=5.7Hz, 2H), 2.54 (s, 3H), 1.36 (m, 1H), 0.88 (s, 9H), 0.38-0.26 (m, 4H),0.03 (s, 6H). ESI-MS m/z=597 (M+H)⁺.

4,6-Dichloro-N-(7-cyclopropyl-1-(6-methylpyridin-3-yl)-1H-indol-5-yl)-N-(2-hydroxyethyl)pyrimidine-5-carboxamide(26H)

A solution of 26G (1.3 g, 2.17 mmol) in 20 mL of methanolic solution ofHCl (5% HCl in MeOH) was stirred at room temperature for 1 h. Methanolwas removed in vacuo, and the residue was dissolved in ethyl acetate.The mixture was washed with saturated aqueous sodium bicarbonate andsaturated aqueous brine. The separated organic layer was dried oversodium sulfate and filtered, and the filtrate was concentrated in vacuoto afford title compound (0.9 g, 86%) as an off-white solid, which wascarried on to the next step without further purification. ¹H NMR (300MHz, DMSO-d₆): δ 8.74 (s, 1H), 8.53 (d, J=2.4 Hz, 1H), 7.81 (dd, J₁=2.7Hz, J₂=8.1 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.42 (d, J=3.3 Hz, 1H), 7.36(d, J=8.1 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H), 6.67 (d, J=3.3 Hz, 1H), 4.84(t, J=5.3 Hz, 1H), 3.92 (t, J=6.0 Hz, 2H), 3.62 (q, J=5.7 Hz, 2H), 2.54(s, 3H), 1.38 (m, 1H), 0.35-0.30 (m, 4H). ESI-MS m/z=484 (M+H)⁺.

4-Chloro-6-(7-cyclopropyl-1-(6-methylpyridin-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(26I)

A solution of 26H (0.9 g, 1.86 mmol) and triethylamine (0.78 mL, 5.6mmol) in acetonitrile (20 mL) was stirred at 80° C. for 16 h. Thereaction was cooled to room temperature, concentrated in vacuo andpartitioned between ethyl acetate and water. The separated organic layerwas dried over sodium sulfate and filtered, and the filtrate wasconcentrated in vacuo to afford title compound (0.7 g, 84%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.83 (s, 1H), 8.60 (d,J=2.4 Hz, 1H), 7.87 (dd, J₁=2.8 Hz, J₂=8.0 Hz, 1H), 7.56 (d, J=2.0 Hz,1H), 7.47 (d, J=3.2 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 6.88 (d, J=1.6 Hz,1H), 6.73 (d, J=3.2 Hz, 1H), 4.74 (t, J=4.8 Hz, 2H), 4.14 (t, J=4.8 Hz,2H), 2.57 (s, 3H), 1.51 (m, 1H), 0.54-0.50 (m, 2H), 0.38-0.30 (m, 2H).ESI-MS m/z=446 (M+H)⁺.

4-Amino-6-(7-cyclopropyl-1-(6-methylpyridin-3-yl)-1H-indol-5-yl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one(26)

A solution of 26I (0.7 g, 1.57 mmol) in 0.5 M ammonia in 1, 4-dioxane(20 mL) was stirred at room temperature for 3 h. The reaction mixturewas concentrated in vacuo, and the residue was partitioned between ethylacetate and water. Separated organic layer was dried over sodium sulfateand filtered, and the filtrate was concentrated in vacuo to give a solidmass, which was triturated with diethyl ether to afford title compound(0.5 g, 68%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.60 (d,J=2.4 Hz, 1H), 8.17 (s, 1H), 7.86 (dd, J₁=4.0 Hz, J₂=8.4 Hz, 1H), 7.63(bs, 2H), 7.47 (d, J=1.8 Hz, 1H), 7.44 (d, J=3.0 Hz, 1H), 7.41 (d, J=8.4Hz, 1H), 6.84 (s, 1H), 6.70 (d, J=3.3 Hz, 1H), 4.64 (t, J=3.9 Hz, 2H),3.97 (t, J=4.5 Hz, 2H), 2.57 (s, 3H), 1.49 (m, 1H), 0.56-0.50 (m, 2H),0.38-0.30 (m, 2H). ESI-MS m/z=427 (M+H)⁺.

Examples 27-36 were prepared using procedures analogous to thosedescribed in Examples 1, 2, 13, 21 and 26 using appropriate startingmaterials.

Exp Structure Analytical Data Mass/Purity 27

¹H NMR (300 MHz, DMSO-d₆): δ 9.06 (s, 2H), 8.18 (s, 1H), 7.82 (d, J =3.3 Hz, 1H), 7.7-7.6 (m, 4H), 7.2 (dd, J₁ = 2.4 Hz, J₂ = 9.0 Hz, 1H),6.81 (d, J = 3.0 Hz, 1H), 4.65 (t, J = 5.1 Hz, 2H), 4.01 (t, J = 5.1 Hz,2H), 3.02 (q, J = 7.8 Hz, 2H), 1.36 (t, J = 7.8 Hz, 3H). ESI-MS m/z =402 (M + H)⁺. HPLC purity: 95% 28

¹H NMR (400 MHz, DMSO-d₆): δ 8.18 (s, 1H), 7.59-7.65 (m, 5H), 7.5 (dd,J₁ = 8.0 Hz, J₂ = 1.6 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H), 7.22 (d, J =8.8 Hz, 1H), 7.15 (dd, J₁ = 8.8 Hz, J₂ = 2.0 Hz, 1H), 6.76 (d, J = 2.8Hz, 1H), 4.65 (t, J = 4.8 Hz, 2H), 4.02 (t, J = 4.4 Hz, 2H), 3.31 (s,3H). ESI-MS m/z = 436 (M + H)⁺; LCMS purity: 98%. 29

¹H NMR (300 MHz, DMSO-d₆): δ 8.18 (s, 1H), 7.63 (bs, 2H), 7.57 (s, 1H),7.44 (d, J = 3.3 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.12 (s, 1H), 7.06(s, 2H), 6.93 (d, J = 6.9 Hz, 1H), 6.63 (d, J = 3.3 Hz, 1H), 4.64 (t, J= 3.9 Hz, 2H), 4.00 (t, J = 3.9 Hz, 2H), 3.74 (s, 3H), 2.42 (s, 3H).ESI-MS m/z = 416 (M + H)⁺; LCMS purity: 96%. 30

¹H NMR (400 MHz, DMSO-d₆): δ 8.17 (s, 1H), 7.65-7.58 (m, 4H), 7.51 (d, J= 2.0 Hz, 1H), 7.10 (dd, J₁ = 2.0 Hz, J₂ = 8.8 Hz, 1H), 6.48 (d, J = 2.8Hz, 1H), 4.68-4.60 (m, 3H), 4.05-3.96 (m, 4H), 3.63-3.54 (m, 2H),2.08-1.86 (m, 4H). ESI-MS m/z: 380 (M + H)⁺; HPLC purity: 95%. 31

¹H NMR (400 MHz, DMSO-d₆): δ 8.17 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H),7.62 (bs, 2H), 7.59 (s, 1H), 7.50 (d, J = 3.2 Hz, 1H), 7.10 (s, 2H),7.05 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 2.8 Hz, 1H), 4.64 (t, J = 4.0 Hz,2H), 4.0 (t, J = 4.4 Hz, 2H), 3.85 (s, 3H), 2.49 (s, 3H). ESI-MS m/z:417 (M + H)⁺; LCMS purity: 96%. 32

¹H NMR (300 MHz, DMSO-d₆): δ 8.91 (s, 2H), 8.18 (s, 1H), 7.72 (d, J =3.3 Hz, 1H), 7.68-7.58 (m, 3H), 7.51 (d, J = 9.0 Hz, 1H), 7.20 (dd, J₁ =1.8 Hz, J₂ = 8.4 Hz, 1H), 6.78 (d, J = 3.0 Hz, 1H), 4.65 (t, J = 3.9 Hz,2H), 4.06-3.98 (m, 5H). ESI-MS m/z = 404 (M + H)⁺. HPLC purity: 95% 33

¹H NMR (400 MHz, DMSO-d₆): δ 8.18 (s, 1H), 7.64-7.58 (m, 3H), 7.54-7.48(m, 3H), 7.41 (dt, J₁ = 2.0 Hz, J₂ = 7.2 Hz, 1H), 7.31 (d, J = 7.2 Hz,1H), 7.10 (dd, J₁ = 2.0 Hz, J₂ = 8.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H),6.70 (d, J = 2.8 Hz, 1H), 4.64 (t, J = 4.4 Hz, 2H), 4.01 (t, J = 4.4 Hz,2H), 2.30-2.39 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). ESI-MS m/z = 400 (M +H)⁺; HPLC purity: 99% 34

¹H NMR (400 MHz, DMSO-d₆): δ 9.05 (d, J = 1.2 Hz, 1H), 8.52 (s, 1H),8.37 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 2.4 Hz, 2H), 7.66 (d, J = 2.0 Hz,1H), 7.63 (bs, 2H), 7.26 (dd, J₁ = 2.0 Hz, J₂ = 8.8 Hz, 1H), 6.84 (d, J= 3.6 Hz, 1H), 4.65 (t, J = 4.4 Hz, 2H), 4.03 (t, J = 4.4 Hz, 2H), 2.56(s, 3H). ESI-MS m/z = 388 (M + H)+. HPLC purity: 94% 35

¹H NMR (300 MHz, DMSO-d₆): δ 8.33 (d, J = 8.7 Hz, 1H), 8.18 (s, 1H),7.95 (d, J = 3.3 Hz, 1H), 7.72- 7.60 (m, 4H), 7.27 (dd, J₁ = 1.8 Hz, J₂= 8.7 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 4.65 (t, J = 5.4 Hz, 2H), 4.02(t, J = 4.5 Hz, 2H), 2.45 (s, 3H). ESI-MS m/z = 377 (M + H)+. LCMSpurity: 87%. 36

¹H NMR (300 MHz, DMSO-d₆): δ 8.18 (s, 1H), 7.65-7.60 (m, 3H), 7.55 (d, J= 8.1 Hz, 1H), 7.51 (d, J = 3.3 Hz, 1H), 7.3 (d, J = 7.5 Hz, 1H),7.13-7.09 (m, 2H), 7.0 (d, J = 8.7 Hz, 1H), 6.7 (d, J = 3.3 Hz, 1H),4.64 (t, J = 4.2 Hz, 2H), 4.01 (t, J = 4.5 Hz, 2H), 3.96 (s, 3H). ESI-MSm/z = 480 (M + H)+. LCMS purity: 95%.

Biological Assay Inhibition of Human DGAT1 Activity In Vitro

Human DGAT1 was expressed in Sf9 insect cells using a baculovirusexpression system. Microsomes were prepared and used as enzyme for invitro inhibition testing in either of two formats measuring productionof coenzyme A or tridecanoylglycerol product, respectively. All stepswere performed at 21-23° C. All data for DGAT1 inhibition by testcompounds were collected under conditions where product formation waslinear with reaction time.

CPM Assay:

For inhibition of CoA product formation, test compounds were prepared in100% DMSO, diluted 100-fold into assay buffer, and 10 uL added to96-well half-area plates (Greiner 675076). An equal volume (10 uL) of 3×enzyme in buffer was added and the components incubated for 30 minutespre-reaction incubation to allow enzyme and test compounds to attainbinding equilibrium. The 3× enzyme mixture contained 30 uM{4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl}aceticacid for fully inhibited control wells. Some assays were performed withinclusion of didecanoylglycerol in the pre-reaction incubation of testcompound and enzyme. DGAT reactions (30 uL) were initiated upon additionof 10 uL of 3× substrate solution. Final reaction conditions consistedof 20 mM HEPES pH 7.5, 2 mM MgCl₂, 1 mM CHAPS, 50 uM didecanoylglycerol,3 uM decanoyl-CoA, 1 ug/mL microsomal protein, and 1% DMSO. Following a60 minute reaction incubation, reactions were stopped and CoA productderivatized with 30 uL of buffer containing 10 uM{4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl}aceticacid and 50 uM 7-diethylamino-3-(4′-maleimidylphenyl)-4-methylcoumarin(CPM). Fluorescence was read using Envision reader at Ex 405 nm/Em 480nm about 30 minutes after addition of final solution. Inhibition wasnormalized to controls containing DMSO or 10 uM{4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl}aceticacid. IC₅₀s were fitted using GraphPad Prism to a sigmoidal doseresponse.

LE Assay:

For inhibition of triacylglycerol product formation, 11 uL reactionswere run in white Polyplate-384 (PerkinElmer6007300) starting with a 30minute pre-reaction incubation of 5 uL of 2.2× enzyme and 1 uL of 100%DMSO containing test compound or control compound,{4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl}aceticacid. Some assays were performed with inclusion of didecanoylglycerol inthe pre-reaction incubation of test compounds and enzyme. Reactions wereinitiated after 30 minute pre-reaction incubation via addition of 5 uLof 2.2× substrate. Final reaction conditions consisted of 50 mM HEPES pH7.5, 2 mM MgCl₂, 1 mM CHAPS, 25 uM didecanoylglycerol, 0.5 uMdecanoyl-CoA, 0.3 nCi/uL [¹⁴C]-decanoyl-CoA or 0.5 nCi/uL[³H]-decanoyl-CoA, 0.05-4 ug/mL microsomal protein, and 1% DMSO.Following 60 minute reaction incubation, reactions were stopped with 40uL of 45% isopropanol and 50 mM sodium carbonate in water and mixed.Extraction of tridecanoylglycerol product was accomplished via additionof 30 uL Microscint-E (Perkin Elmer) and 2 hours of incubation (sealed).Plates were read on a Microbeta Microplate reader. Inhibition wasnormalized to controls containing DMSO or 10 uM{4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl}aceticacid. IC₅₀s were fitted using GraphPad Prism to a sigmoidal doseresponse.

Biological Data

Exemplified compounds of the present invention were tested in one ormore DGAT assays described above and were found to be inhibitors ofDGAT1 with IC₅₀<10 μM. Data for specific examples tested in the humanDGAT1 lipid extraction (LE) assays are listed below in Table 1.

TABLE 1 hDGAT LE Example # IC₅₀ (nM) 1 39.1 2 0.5 3 14.7 4 31.3 5 6.8 625 7 3.2 8 2.9 9 9.7 10 7.9 11 13.3 12 1.8 13 101.1 14 14.5 15 6.8 164.8 17 0.3 18 24.1 19 11.2 20 4.2 21 16.3 22 1.8 23 16.1 24 82.2 25 9326 3.4 27 49.7 28 1.7 29 8.5 30 6.1 31 14.6 32 38.1 33 2.5 34 15.8 35 7536 1.8

1. A compound which is:

or a pharmaceutically acceptable salt thereof.
 2. A compound which is:


3. A pharmaceutical composition comprising the compound orpharmaceutically acceptable salt according to claim 1 and apharmaceutically acceptable excipient.
 4. A pharmaceutical compositioncomprising the compound according to claim 2 and a pharmaceuticallyacceptable excipient.
 5. A method of treating obesity comprisingadministering to a human in need thereof an effective amount of thecompound or pharmaceutically acceptable salt according to claim
 1. 6. Amethod of treating obesity comprising administering to a human in needthereof an effective amount of the compound according to claim
 2. 7. Amethod of treating acne comprising administering to a human in needthereof an effective amount of the compound or pharmaceuticallyacceptable salt according to claim
 1. 8. A method of treating acnecomprising administering to a human in need thereof an effective amountof the compound according to claim
 2. 9. A method of treatingnon-alcoholic steatohepatitis comprising administering to a human inneed thereof an effective amount of the compound or pharmaceuticallyacceptable salt according to claim
 1. 10. A method of treatingnon-alcoholic steatohepatitis comprising administering to a human inneed thereof an effective amount of the compound according to claim 2.11. A method of treating obesity comprising administering to a human inneed thereof an effective amount of the pharmaceutical compositionaccording to claim
 3. 12. A method of treating obesity comprisingadministering to a human in need thereof an effective amount of thepharmaceutical composition according to claim
 4. 13. A method oftreating acne comprising administering to a human in need thereof aneffective amount of the pharmaceutical composition according to claim 3.14. A method of treating acne comprising administering to a human inneed thereof an effective amount of the pharmaceutical compositionaccording to claim
 4. 15. A method of treating non-alcoholicsteatohepatitis comprising administering to a human in need thereof aneffective amount of the pharmaceutical composition according to claim 3.16. A method of treating non-alcoholic steatohepatitis comprisingadministering to a human in need thereof an effective amount of thepharmaceutical composition according to claim 4.